Pyridylpyrrole compounds useful as interleukin-and TNF antagonists

ABSTRACT

The present invention provides a compound of the formula:                    
     and its pharmaceutically acceptable salts, wherein R 1 , R 2 , R 3 , R 4 , R 5  and m are as defined in claim 1. The present invention also provides processes for the preparation thereof, the use thereof in treating cytokines mediated diseases and/or cell adhesion molecules (CAMs) mediated diseases and pharmaceutical compositions for use in such therapy.

This application is a 371 of PCT/IB97/00703 filed May 15, 1997, now WO98/02430 Jan. 22, 1998.

TECHNICAL FIELD

This invention relates to novel pyridylpyrrole compounds, processes forthe preparation thereof, the use thereof in treating cytokines mediateddiseases and/or cell adhesion molecules mediated diseases, andpharmaceutical compositions for use in such therapy.

BACKGROUND ART

Cytokines possess a multitude of regulatory and inflammatory effects.Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis (RA), osteoarthritis (OA),endotoxemia and/or toxic shock syndrome, other acute and chronicinflammatory disease states such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease (IBD), tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis andacute synovitis. Recent evidence also links IL-1 activity to diabetes.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including RA, rheumatoidspondylitis, OA, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxin shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome (ARDS), cerebral malaria,chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoisosis, bone resorption diseases, reperfision injury, graft vs.host reaction, allograft rejections, fever and myalgias due to infectionsuch as influenza, cachexia secondary to infection or malignancy,cachexia, secondary to acquired immune deficiency syndrome (AIDS), ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis or pyresis. The concept of anti-TNF therapyhas been validated by the demonstration that soluble TNF receptor andneutralizing monoclonal antibodies (MAbs) against TNF showed therapeuticefficacy in a variety of preclinical and clinical studies (e.g.,Elliott, M. J. et al., The Lancet, 1994, 344, 1125. Dullemen, H. M. V.et al., Gastroenterology, 1995, 109, 129.)

Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. IL-8 is produced by several cell types includingneutrophils, mononuclear cells, fibroblasts, endothelial cells,epithelial cells and keratinocytes. Elevated IL-8 levels have beenreported in joint fluids in RA, gouty arthritis, psoriatic scale andARDS. Its production from endothelial cells is induced by IL-1, TNF orlipopolysachharide (LPS). IL-8 has been shown to have chemoattractantproperties for neutrophils, T-lymphocytes and basophils. In addition, itpromote angiogenesis as well as neutrophil activation, includinglysozomal enzyme release and respiratory burst. IL-8 has also been shownto increase the surface expression of Mac-1 (CD 11b/CD18) onneutrophils, this may contribute to increased adhesion of theneutrophils to vascular endothelial cells. Many diseases arecharacterized by massive neutrophil infiltration. Conditions associatedwith an increased IL-8 production would benefit by compounds which aresuppressive of IL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues, and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

Cellular movement and adhesion are a fundamental biological response toexternal stimuli. During an inflammatory response, leukocytes must leavethe plasma compartment and migrate to the point of antigenic insult. Themechanism of this migratory event is a complex interplay between solublemediators and membrane-bound cellular adhesion molecules. Solublecellular chemotactic factors, which are produced in the damaged tissueby a variety of resident cells, set up a chemical concentration gradientout to the plasma compartment. Interaction of these factors with theirreceptors on leukocytes leads to a directional migration of theleukocytes toward increasing concentrations of the chemotactic factor.Simultaneously, various adhesion molecules are upregulated on theleukocyte which mediate the initial rolling on the endothelial tissue,binding to a specific ligand on the activated endothelial tissue, andfinally migration between endothelial cells into the tissue. The stepsin this cascade of events are mediated by the interaction of specificcell surface protein, termed “cell adhesion molecules (CAMs)”.E-selectin (ELAM-1, endothelial leukocyte adhesion molecule-1), ICAM-1(intercellular adhesion molecule-1), and VCAM-1 (vascular cell adhesionmolecule-1) are three major adhesion molecules whose expression onendothelial cells is upregulated upon treatment with inflammatorystimuli. ICAM-1 is expressed at low levels on resting endothelium and ismarkedly induced in response to cytokines such as IL-1, TNF andinterferon-γ (IFN-γ). VCAM-1 is not expressed in resting endothelium butis induced by IL-1, TNF and IL-4. Induction of both ICAM-1 and VCAM-1occurs 4 to 6 hours after cytokine treatment and cell surface expressionremains elevated for up to 72 hours after treatment with cytokines. Onthe other hand, induction of transcription of the E-selectin gene bycytokines such as IL-1 and TNF results in an increase in the expressionon the surface of endothelial cells peaking approximately 4-6 hoursafter challenge, and returns toward a basal level of expression by 24hours.

The concept of anti-CAMs therapy has been validated by the demonstrationthat MAbs against ICAM-1 and antisense oligonucleotide against ICAM-1showed therapeutic efficacy in a variety of preclinical and clinicalstudies (A. F. Kavanaugh et al., Arthritis Rhetun, 1994, 37, 992; C. E.Haug et al., Transplantation, 1993, 55, 766; and J. E. Jr. Sligh et al.,Proc. Natl. Acad. Sci., 1993, 90, 8529). Further support comes from thereports of the in vivo activity of sLeX and related carbohydrates,antagonists of E-selectin mediated adhesion (M. S. Mulligan et al.,Nature, 1993, 364, 149-151). Thus, the potential therapeutic targets forCAMs inhibitors range from, but are not limited to, RA, IBD andpsoriasis to ischemia/reperfusion injury, autoimmune diabetes, organtransplantation, ARDS, tumor metastases and AIDS, as is evident from themany ongoing development activities. The regulation of the functions ofCAMs is of benefit in controlling, reduction and alleviating many ofthese disease states. There remains a need for treatment, in this field,for compounds which are capable of inhibiting cytokines productionand/or CAMs expression. The pyridylpyrroles of the present inventionhave been shown in an in vitro assay to inhibit cytokines productionand/or CAMs expression.

International Publication No. WO 95/18122 discloses2-heteroaryl-3-cyanopyrrole compounds having agrochemical activities.

British Patent No. GB1311336 discloses quaternary salts ofpyrrolylpyridine compounds (e.g.,4,4′-(3,4-dimethylpyrrol-2,5-diyl)bis(1-n-heptylpyridinium bromide)having antibacterial and fungal properties.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a compound of the formula:

and its pharmaceutically acceptable salts, wherein

R¹ is selected from the following:

(a) hydrogen, R⁶—, R⁶—NH—, hydroxy-R⁶— or R⁶—O—R⁶—;

(b) R⁶—CO—, R⁶—O—CO—R⁶—, carboxy-R⁶—, NH₂—CO— or R⁶—NH—CO—; and

(c) Ar—, Ar—R⁶—, Ar—NH—or Ar—CO—;

wherein Ar is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, pyrrolyl, indolyl, benzothienyl and benzofuryl, the arylor heteroaryl groups being optionally substituted with one or twosubstituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro, hydroxy, amino, R⁶—NH—,(R⁶)₂N—, halo, formyl, halo-substituted phenoxy, halo-substitutedphenyl, C₁₋₄ alkyl-substituted phenoxy, halo-substituted phenylthio,C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylthio and C₁₋₄ alkyl-SO—; and

wherein R⁶ is C₁₋₆alkyl optionally substituted by up to four halogenatoms;

R² and R⁴ are independently selected from the following:

(d) hydrogen, halo, R⁶—, C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxy-R⁶—,R⁶—O—R⁶—, mercapto-R⁶—, R⁶—S—R⁶—, —NH₂, R⁶—NH—, R⁶)₂—N—, R⁶—O—, R⁶—S—,R⁶—SO— and R⁶—SO₂—;

(e) 1,4-dioxa-8-azaspiro[4,5]-decanyl,

wherein Y is selected from —NH, —N—R⁶, —N—Ar, O and S; l is 0, 1, 2, 3,4 or 5; n is independently 0, 1 or 2; and Ar is as defined above;

(f) Ar—, Ar—R⁶—, Ar—C₂₋₆ alkenyl, Ar—C₂₋₆ alkynyl, Ar—O—, Ar—O—R⁶—,Ar—R⁶—O—, Ar—S—, Ar—R⁶—S—, Ar—NH—, (Ar)₂—R⁶—, Ar—R⁶—NH— or (Ar)₂—N—;

(g) R⁶—CO—, —NO₂, NH₂—CO—, R⁶—NH—CO—, (R⁶)₂—N—CO—, Ar—CO—,(Ar—R⁶)₂-N—CO—, Ar—R⁶—CO—, Ar—NH—CO— or Ar—R⁶—NH—CO—; and

(h) R⁶—CO—NH—, Ar—CO—NH—, Ar—R⁶—CO—NH—or H₂N—CO—NH—;

wherein Ar and R⁶ are as defined above, provided that R² is not Ar;

R³ is selected from the following:

(i) C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, hydroxy-R⁶—, R⁶—O—R⁶—, R⁶—S—R⁶—,Ar—, NH₂—R⁶— or R⁶—NH—R⁶;

(j) formyl, carboxy, carboxy-R⁶—, tetrazolyl, triazolyl, imidazolyl,oxazolyl, thiazolyl, R⁶—CO—, C₂₋₆ alkenyl—CO—, C₂₋₆ alkynyl—CO—,R⁶—CO—R⁶—, C₂₋₆ alkenyl—CO—R⁶—, C₂₋₆alkynyl—CO—R⁶—, R⁶—O—CO—,R⁶—O—CO—R⁶—, R⁶—S—CO—, C₂₋₆ alkenyl—O—CO—, C₂₋₆ alkynyl—O—CO— orR⁶—O—R⁶—CO—;

(k) R⁶—CO—NH—, Ar—CO—NH—, Ar—R⁶—CO—NH—, —NH₂, R⁶—NH—, (R⁶)₂—N—,H₂N—CO—NH—, R⁶—NH—CO—NH—, (R⁶)₂—N—CO—NH—, Ar—NH—CO—NH—, (Ar)₂—N—CO—NH—,HO—N═CH—R⁶—, R⁶O—N═CH— or R⁶O—N═CH—R⁶—;

(l) R⁶—SO—, R⁶—NH—SO₂— R⁶—SO₂—, —SO₂NH₂, —SONH₂, R⁶—NH—SO—, Ar—SO—,Ar—R⁶SO—, Ar—SO₂—, C₂₋₆ alkenyl-SO₂—, C₂₋₆ alkynyl-SO₂—, Ar—R⁶—SO₂—,Ar—NH—SO₂—, Ar—R⁶—NH—SO₂—, Ar—NH—SO— or Ar—R⁶—NH—SO—; and

(m) Ar—CO—, Ar—R⁶—CO—, Ar—C₂₋₆ alkenyl—CO—, Ar—C₂₋₆ alkynyl—CO—,Ar—O—CO—, Ar—O—R⁶—CO—, Ar—S—R⁶—CO—, Ar—R⁶—O—CO—, Ar—R⁶—S—CO—, (Ar)₂—C₂₋₆alkenyl-CO—, (Ar)₂—C₂₋₆ alkynyl-CO—, (Ar)₂—R⁶—O—CO— or (Ar)₂—R⁶—S—CO—;

wherein Ar and R⁶ are as defined above; or

two of R², R³ and R⁴ together form a group of the formula—A¹—B¹—A²—B²—A³— which, together with the carbon atoms to which A¹ andA³ are attached, defines a ring having 5 to 8 ring atoms, the ringoptionally being substituted with one or two substituents selected fromhydroxy, R⁶, C₁₋₄ alkoxy and Ar, wherein A¹, A² and A³ are independentlydirect bond or C₁₋₄ alkylene and B¹ and B² are independently directbond, O, S, SO, CO, NH or NR⁶;

R⁵ is independently selected from the following:

(n) hydrogen, halo, R⁶—, hydroxy-R⁶— or R⁶—O—R⁶—;

(o) Ar—, Ar—R⁶—, Ar—O—, Ar—S—, Ar—NH— or Ar—CO—; and

(p) R⁶—CO—, R⁶—O—CO— or R⁶—NH—CO—; or

two of R⁵ which are attached to adjacent carbon atoms on the pyridinering complete a fused benzene ring, the benzene ring being optionallysubstituted with one or two substituents selected from C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro,hydroxy, amino and halo;

wherein R⁶ and Ar are as defined above;

m is 0, 1, 2, 3 or 4; and

the nitrogen atom of the pyridyl ring attached to the 5-position of thepyrrole ring is optionally replaced by a N oxide group.

The present invention also provides a pharmaceutical composition for thetreatment or alleviation of cytokine-mediated diseases or CAMs mediateddiseases, which comprises a therapeutically effective amount of acompound of said formula (I) or its pharmaceutically acceptable carrier.

The present invention further provides a method for the treatment ofdisease conditions caused by cytokine-mediator or CAMs mediator, in amammalian subject, which comprises administering to said subject atherapeutically effective amount of a compound of the formula (I).

The present invention also provides a pharmaceutical composition for thetreatment or alleviation of cytokine-mediated diseases or CAMs mediateddiseases, which comprises a therapeutically effective amount of acompound of the formula (I):

and its pharmaceutically acceptable salts, wherein

R¹ is selected from the following:

(a) hydrogen, R⁶—, R⁶—NH—, hydroxy-R⁶— or R⁶—O—R⁶—;

(b) R⁶—CO—, R⁶—O—CO—R⁶—, carboxy-R⁶—, NH₂—CO— or R⁶—NH—CO—; and

(c) Ar—, Ar—R⁶—, Ar—NH— or Ar—CO—;

wherein Ar is selected from phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, pyrrolyl, indolyl, benzothienyl and benzofuryl, the arylor heteroaryl groups being optionally substituted with one or twosubstituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halo-substitutedC₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro, hydroxy, amino, R⁶—NH—,(R⁶)₂N—, halo, formyl, halo-substituted phenoxy, halo-substitutedphenyl, C₁₋₄ alkyl-substituted phenoxy, halo-substituted phenylthio,C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylthio and C₁₋₄ alkyl-SO—; and

wherein R⁶ is C₁₋₆ alkyl optionally substituted by up to four halogenatoms;

R² and R⁴ are independently selected from the following:

(d) hydrogen, halo, R⁶—, C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxy-R⁶—,R⁶—O—R⁶—, mercapto-6—, R⁶—S—R⁶—, —NH₂, R⁶—NH—, (R⁶)₂—N—, R⁶—O—, R⁶—S—,R⁶—SO—and R⁶—SO₂;

(e) 1,4-dioxa-8-azaspiro[4,5]-decanyl,

wherein Y is selected from —NH, —N—R⁶, —N—Ar, O and S; l is 0, 1, 2, 3,4 or 5; n is independently 0, 1 or 2; and Ar is as defined above;

(f) Ar—, Ar—R⁶—, Ar—C₂₋₆ alkenyl, Ar—C₂₋₆ alkynyl, Ar—O—, Ar—O—R⁶—,Ar—R⁶—O—, Ar—S—, Ar—R⁶—S—, Ar—NH—, (Ar)₂—R⁶—, Ar—R⁶—NH— or (Ar)₂—N—;

(g) R⁶—CO—, —NO₂, NH₂—CO—, R⁶—NH—CO—, (R⁶)₂—N—CO—, Ar—CO—,(Ar—R⁶)₂—N—CO—, Ar—R⁶—CO—, Ar—NH—CO— or Ar—R⁶—NH—CO—; and

(h) R⁶—CO—NH—, Ar—CO—NH—, Ar—R⁶—CO—NH—or H₂N—CO—NH—;

wherein Ar and R⁶ are as defined above, provided that R² is not Ar;

R³ is selected from the following:

(i) C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, hydroxy-R⁶—, R⁶—O—R⁶—, R⁶—S—R⁶—,Ar—, NH₂R⁶— or R⁶NH—R⁶;

(j) cyano, H₂N—CO—, formyl, carboxy, carboxy-R⁶—, tetrazolyl, triazolyl,imidazolyl, oxazolyl, thiazolyl, R⁶—CO—, C₂₋₆ alkenyl-CO—, C₂₋₆alkynyl-CO—, R⁶—CO—R⁶—, C₂₋₆ alkenyl-CO—R⁶—, C₂₋₆ alkynyl-CO—R⁶—,R⁶—O—CO—, R⁶—CO—R⁶—, R⁶—S—CO—, C₂₋₆ alkenyl—O—CO—, C₂₋₆ alkynyl—O—CO— orR⁶—O—R⁶—CO—;

(k) R⁶—CO—NH—, Ar—CO—NH—, Ar—R⁶—CO—NH—, —NH₂, R⁶—NH—, (R⁶)₂—N—,H₂N—CO—NH—, R⁶—NH—CO—NH—, (R⁶)—N—CO—NH—, Ar—NH—CO—NH—, (Ar)₂—N—CO—NH—,HO—N═CH—R⁶—, R⁶O—N═CH— or R⁶O—N═CH—R⁶—;

(l) R⁶—SO—, R⁶—NH—SO₂—R⁶—SO₂—, —SO₂NH₂, —SONH₂, R⁶—NH—SO—, Ar—SO—,Ar—R⁶—SO—, Ar—SO₂—, C₂₋₆ alkenyl-SO₂—, C₂₋₆ alkynyl-SO₂—, Ar—R⁶—SO₂—,Ar—NH—SO₂—, NH—SO₂—, Ar—NH—SO— or Ar—R⁶—NH—SO—; and

(m) Ar—CO—, Ar—R⁶—CO—, Ar—C₂₋₆ alkenyl-CO—, Ar—C₂₋₆ alkynyl-CO—,Ar—O—CO—, Ar—O—R⁶—CO—, Ar—S—R⁶—CO—, Ar—R⁶—O—CO—, Ar—R⁶—S—CO—, (Ar)₂—C₂₋₆alkenyl-CO—, (Ar)₂—C₂₋₆ alkynyl-CO—, (Ar)₂—R⁶—O—CO— or (Ar)₂—R⁶—S—CO—;

wherein Ar and R⁶ are as defined above; or

two of R², R³ and R⁴ together form a group of the formula—A¹—B¹—A²—B²—A³— which, together with the carbon atoms to which A¹ andA³ are attached, defines a ring having 5 to 8 ring atoms, the ringoptionally being substituted with one or two substituents such ashydroxy, R⁶, C₁₋₄ alkoxy or Ar, wherein A¹, A² and A³ are independentlydirect bond or C₁₋₄ alkylene and B¹ and B² are independently directbond, O, S, SO, CO, NH or NR⁶;

R⁵ is independently selected from the following:

(n) hydrogen, halo, R⁶—, hydroxy-R⁶— or R⁶—O—R⁶—;

(o) Ar—, Ar—R⁶—, Ar—O—, Ar—S—, Ar—NH— or Ar—CO—; and

(p) R⁶—CO—, R⁶—O—CO— or R⁶—NH—CO—; or

two of R⁵ which are attached to adjacent carbon atoms on the pyridinering complete a fused benzene ring, the benzene ring being optionallysubstituted with one or two substituents selected from C₁₋₄ alkyl,halo-substituted C₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro,hydroxy, amino and halo;

wherein R⁶ and Ar are as defined above;

m is 0, 1, 2, 3 or 4; and

the nitrogen atom of the pyridyl ring attached to the 5-position of thepyrrole ring is optionally replaced by a N oxide group.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “C₁₋₆ alkyl” means straight or branched chainsaturated radicals of 1 to 6 carbon atoms, including, but not limited tomethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl,tertiary-butyl, and the like.

As used herein, the term “C₂₋₆ alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

As used herein, the term “halo” means fluoro, chloro, bromo and iodo.

As used herein, the term “N oxide group” means one represented by thefollowing formula:

As used herein, the term “equivalent of R^(2a)—C(O)—CH₂—R⁷” meanscompounds with similar reactivity to R^(2a)—C(O)—CH₂—R⁷, or compoundswhich can be transformed to R^(2a)—C(O)—CH₂—R⁷ in situ, such as enamineequivalent R^(2a)—C(NH₂)═CH—R⁷, or enolether equivalentR^(2a)—C(OR^(3a))═CH—R⁷.

In the formula (I), a substituent of substituted R⁶ (for example,hydroxy-R⁶—, carboxy-R⁶—, R⁶—O—R⁶—, etc.) may be attached to any carbonatom of the R⁶.

In the group “(Ar)₂—R⁶—”, two of Ar may be the same or different fromeach other, and may be attached to a same carbon atom or differentcarbon atoms of R⁶.

A preferred group of compounds of this invention includes the compoundof the formula (I) wherein R¹ is selected from group (a); R² is selectedfrom group (d), (e) or (f), provided that R² is not Ar; R³ is selectedfrom groups (i), (j), (k) and (m), provided that R³ is not Ar,tetrazolyl, triazolyl, imidazolyl, oxazolyl nor thiazolyl; R⁴ isselected from group (d), (e) or (f); and R⁵ is selected from group (n);and m is 0, 1 or 2.

A more preferred group of compounds of this invention includes thecompounds of formula (I) wherein R¹ is hydrogen, C₁₋₄ alkyl, C₁₋₄alkylamino, halo substituted C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl, C₁₋₄alkoxyalkyl or halo C₁₋₄ alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, R⁶—,hydroxy-R⁶— or R⁶—O—R⁶—; R³ is C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo,hydroxy-R⁶—, R⁶—O—R⁶—, R⁶—S—R⁶—, R⁶—NH—R⁶—, formyl, carboxy,carboxy-R⁶—, R⁶—CO—, C₂₋₆ alkenyl-CO—, C₂₄ alkynyl-CO—, R⁶—CO—R⁶—, C₂₋₆alkenyl-CO—R⁶—, C₂₋₆ alkynyl-CO—R⁶—, R⁶—O—CO—, R⁶—O—CO—R⁶—, R⁶—S—CO—,C₂₋₄ alkenyl—O—CO— or R⁶—O—R⁶—CO—; R⁴ is hydrogen, R⁶—, morpholinooptionally substituted by one, two or three C₁₋₄ alkyl or phenyl,1-piperidinyl optionally substituted by one, two or three C₁₋₄ alkyl orphenyl, 4-piperazinyl optionally substituted at its 1-position by C₁₋₄alkyl or phenyl, pyridyl, quinolyl, furyl, thienyl or pyrrolyl, phenyl,naphthyl, pyridyl, quinolyl, thienyl, furyl, pyrrolyl, indolyl,benzothienyl or benzofuryl, and wherein said phenyl, naphthyl, pyridyl,quinolyl, thienyl, furyl, pyrrolyl, indolyl, benzothienyl or benzofurylmay optionally be substituted with one or two substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, halo, formyl, C₁₋₄halo-substituted alkyl, halo-substituted phenoxy, halo-substitutedphenylthio, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylthio and C₁₋₄ alkyl-SO—; Rsis hydrogen, halo, C₁₋₄ alkyl or halo substituted C₁₋₄ alkyl; and m is 0or 1.

A more preferred group of compounds of this invention includes thecompounds of formula (I) wherein R¹ is hydrogen, C₁₋₄ alkyl or C₁₋₄alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, C₁₋₄ alkyl optionallysubstituted by halo, hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ isC₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, formyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkylcarbonyl-C₁₋₄alkyl, C₁₋₄ alkoxy-carbonyl, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkyl, C₂₋₄alkenyloxycarbonyl or C₁₋₄ alkyloxy-C₁₋₄-alkylcarbonyl; R² and R³ are atthe 4 and 3 positions of the pyrrole ring, respectively; R⁴ is C₁₋₄alkyl, morpholino, dimethylmorpholino, 1-piperidinyl, 4-piperazinyloptionally substituted at its 1-position by C₁₋₄ alkyl, phenyl orpyridyl, phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl orpyrrolyl, and wherein said phenyl, naphthyl, pyridyl, quinolyl, thienyl,furyl or pyrrolyl may optionally be substituted with one or twosubstituents independently selected from C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo, formyl, fluorophenoxy, methoxycarbonyl, ethoxycarbonyl,methylthio, ethylthio and methyl-SO—; and R⁵ is hydrogen or halo.

A more preferred group of compounds of this invention includes thecompounds of formula (I) wherein R¹ is hydrogen, C₁₋₄ alkyl or C₁₋₄alkoxy-C₁₋₄ alkyl; R² is C₁₋₄ alkyl optionally substituted by halo,hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ is C₂₋₄ alkenyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, formyl, C₁₋₄ alkylcarbonyl,C₁₋₄ alkylcarbonyl-C₁₋₄ alkyl, C₁₋₄ alkoxy-carbonyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl; R⁴ is morpholino, 1-piperidinyl,4-phenyl-piperazin-1-yl, 1-(2-pyridyl)-piperazin4-yl, pyridyl, phenyl,naphthyl, pyrrolyl, furyl or thienyl, and wherein said pyridyl, phenyl,naphthyl, pyrrolyl, furyl or thienyl may optionally be substituted withC₁₋₄ alkoxy, halo, formyl, 4-fluorophenoxy, methoxycarbonyl,ethoxycarbonyl or methylthio; and R⁵ is hydrogen.

A preferred group of compounds of this invention includes the compoundof the formula (I) wherein R³ at the 3-position and R⁴ at the 2-positiontogether form a group of the formula —A¹—B¹—A²—B²—A³— which, togetherwith the carbon atoms to which A¹ and A³ are attached, defines a ringhaving 5 to 8 ring atoms, the ring optionally being substituted with oneor more substituents selected from hydroxy, R⁶, C₁₋₄ alkoxy and Ar,wherein A₁, A² and A³ are independently direct bond or C₁₋₄ alkylene andB¹ and B² are independently direct bond, O, S, SO, CO, NH or NR⁶.

Among these, a more preferred group of compounds of this inventionincludes the compound of the formula (I) wherein —A¹—B¹—A²—B²—A³— isselected form —CO—(CH₂)₃—, —CO—(CH₂)₂—, —CO—CH₂—C(CH₃)₂—CH₂—,—CO—(CH₂)₂—C(CH₃)₂, —CO—(CH₂)₄—, —CO—CH₂—CH(CH₃)—CH₂—,—CO—O—CH(CH₃)—CH₂— and —CO—CH₂—S—CH₂—.

Also, a particularly preferred compound of the invention includes thecompound of formula (I) wherein R¹ is hydrogen, methyl or methoxyethyl;R² is methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl,phenyl, n-propyl, isopropyl, n-bytyl, isobutyl, methoxymethyl,nitrophenyl, hydroxymethyl or pyridyl; R³ is acetyl, propanoyl,pentanoyl, ethoxycarbonyl, methoxycarbonyl, formyl, methanesulfonyl,hydroxyethyl, hydroxymethyl, benzyloxycarbonyl, allyloxycarbonyl,carboxyl, methylethoxycarbonyl, 1,1-dimethylethoxycarbonyl,propoxycarbonyl, butoxycarbonyl or methoxyethoxycarbonyl; R² and R³ areat the 4 and 3 positions of the pyrrole ring, respectively; R⁴ ismethyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,naphthyl, pyridyl, quinolyl, thienyl, phenyl, hydrogen, morpholino,1-piperidinyl, (1-phenyl)-4-piperazinyl or (2-pyridyl)-4-piperazinyl;and R⁵ is hydrogen.

Among the compounds of the formula (I), the most preferred compound isone of the following:

3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole;

3-acetyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole;

3-acetyl-2,5-di(4-pyridyl)4-trifluoromethyl-1H-pyrrole;

3-methoxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole;

3-acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole;

3-acetyl-4-methyl-2-phenyl-5-(4-pyridyl)-1lH-pyrrole;

3-methyl4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole;

3-acetyl-2-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-acetyl-2-(2-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

4-Oxo-2-(4-pyridyl)-3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole;

3,6-Dimethyl4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole;

4-Oxo-2-(4-pyridyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole;

3-Acetyl-2-{(4-methoxycarbonyl)phenyl}-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-4-methyl-2-(1-piperidinyl)-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-4-methyl-2-(4-phenylpiperazin-1-yl)-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-2-(3-chloro-4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-2-(4-chlorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-2-(4-methoxyphenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole; and

3-Acetyl-4-methyl-2-(4-morpholino)-5-(4-pyridyl)-1H-pyrrole.

The present invention also provides a process for preparing a compoundof the formula;

wherein R¹, R⁵ and m are defined in claim 1; R^(2a) are independentlyhydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, Ar or Ar—C₁. alkyl;and R⁷ is —C(O)R^(3a), —C(O)OR^(3a), —CN or —SO₂R^(3a), wherein R^(3a)is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Ar or Ar—C₁₋₄alkyl,

which comprises reacting a compound of the formula:

 or its equivalent of this compound, with a compound of the formula:

and amine R¹NH₂ in a reaction-inert solvent.

The compounds of the formula (I) of the present invention can be used asan active ingredient for the treatment or alleviation of asthma,arthritis, inflammatory bowel disease, sepsis, septic shock, rhinitis,inflammation of organs, AIDS, various inflammatory diseases,cardiovascular diseases, psoriasis, thrombosis, crohn's disease,cachexia, viral infections, gout, graft vs host disease, transplantrejection and the like.

Preferred pharmaceutical composition of this invention are those of theformula (I), wherein R¹ is selected from group (a); R² is selected fromgroup (d), (e) or (f), provided that R² is not Ar; R³ is selected fromgroups (i), (j), (k) and (m), provided that R³ is not Ar, tetrazolyl,triazolyl, imidazolyl, oxazolyl nor thiazolyl; R⁴ is selected from group(d), (e) or (f); and R⁵ is selected from group (n); and m is 0, 1 or 2.

More preferred pharmaceutical composition of this invention are those ofthe formula (I), wherein R¹ is hydrogen, C₁₋₄ alkyl, C₁₋₄ alkylamino,halo substituted C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxyalkyl orhalo C₁₋₄ alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, R⁶—, hydroxy-R⁶— orR⁶O—R⁶—; R³ is C₂₋₆ alkenyl, C₂₋₄ alkynyl, halo, hydroxy-R⁶—, R⁶O—R⁶—,R⁶—S—R⁶—, R⁶—NH—R⁶—, formyl, carboxy, carboxy-R⁶—, R⁶—CO—, C₂₋₆alkenyl-CO—, C₂₋₆ alkynyl-CO—, R⁶—CO—R⁶—, C₂₋₄ alkenyl-CO—R⁶—, C₂₋₆alkynyl-CO—R⁶—, R⁶O—CO—, R⁶—O—CO—R⁶—, R⁶—S—CO—, C₂₋₆ alkenyl—O—CO— orR⁶O—R⁶—CO—; R⁴ is hydrogen, R⁶—, morpholino optionally substituted byone, two or three C₁₋₄ alkyl or phenyl, 1-piperidinyl optionallysubstituted by one, two or three C₁₋₄ alkyl or phenyl, 4-piperazinyloptionally substituted at its 1-position by phenyl or C₁₋₄ alkyl,pyridyl, quinolyl, furyl, thienyl or pyrrolyl, phenyl, naphthyl,pyridyl, quinolyl, thienyl, furyl, pyrrolyl, indolyl, benzothienyl orbenzofuryl, and wherein said phenyl, naphthyl, pyridyl, quinolyl,thienyl, furyl, pyrrolyl, indolyl, benzothienyl or benzofuryl mayoptionally be substituted with one or two substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, halo, formyl, C₁₋₄halo-substituted alkyl, halo-substituted phenoxy, halo-substitutedphenylthio, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylthio and C₁₋₄ alkyl-SO—; R⁵is hydrogen, halo, C₁₋₄ alkyl or halo substituted C₁₋₄ alkyl; and m is 0or 1.

Furthermore preferred pharmaceutical composition of this invention arethose of the formula (I), wherein R¹ is hydrogen, C₁₋₄ alkyl or C₁₋₄alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, C₁₋₄ alkyl optionallysubstituted by halo, hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ isC₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄alkyl, formyl, carboxy, C₁₋₄ alkylcarbonyl, C₁₋₄ alkylcarbonyl-C₁₋₄alkyl, C₁₋₄ alkoxy-carbonyl, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkyl, C₂₋₄alkenyloxycarbonyl or C₁₋₄ alkyloxy-C₁₋₄-alkylcarbonyl; R² and R³ are atthe 4 and 3 positions of the pyrrole ring, respectively; R⁴ is C₁₋₄alkyl, morpholino, dimethylmorpholino, 1-piperidinyl, 4-piperazinyloptionally substituted at its 1-position by C₁₋₄ alkyl, phenyl orpyridyl, phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl orpyrrolyl, and wherein said phenyl, naphthyl, pyridyl, quinolyl, thienyl,furyl or pyrrolyl may optionally be substituted with one or twosubstituents independently selected from C₁₋₄ alkyl, hydroxy, C₁₋₄alkoxy, halo, formyl, fluorophenoxy, methoxycarbonyl, ethoxycarbonyl,methylthio, ethylthio and methyl-SO—; and Rs is hydrogen or halo.

Much furthermore preferred pharmaceutical composition of this inventionare those of the formula (I), wherein R¹ is hydrogen, C₁₋₄ alkyl or C₁₋₄alkoxy-C₁₋₄ alkyl; R² is C₁₋₄ alkyl optionally substituted by halo,hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ is C₂₋₄ alkenyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, formyl, C₁₋₄ alkylcarbonyl,C₁₋₄ alkylcarbonyl-C₁₋₄ alkyl, C₁₋₄ alkoxy-carbonyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl; R⁴ is morpholino, 1-piperidinyl,4-phenyl-piperazin-1-yl, 1-(2-pyridyl)-piperazin-4-yl, pyridyl, phenyl,naphthyl, pyrrolyl, furyl or thienyl, and wherein said pyridyl, phenyl,naphthyl, pyrrolyl, furyl or thienyl may optionally be substituted withC₁₋₄ alkoxy, halo, formyl, 4-fluorophenoxy, methoxycarbonyl,ethoxycarbonyl or methylthio; and R⁵ is hydrogen.

Another preferred pharmaceutical composition of this invention are thoseof the formula (I), wherein R³ at the 3-position and R⁴ at the2-position together form a group of the formula —A¹—B¹—A²—B²—A³— which,together with the carbon atoms to which A¹ and A³ are attached, definesa ring having 5 to 8 ring atoms, the ring optionally being substitutedwith one or more substituents selected from hydroxy, R⁶, C₁₋₄ alkoxy andAr, wherein A¹, A² and A³ are independently direct bond or C₁₋₄ alkyleneand B¹ and B² are independently direct bond, O, S, SO, CO, NH or NR⁶.

Among these, more preferred pharmaceutical composition of this inventionare those of the formula (1), wherein —A¹—B¹—A²—B²—A³— is selected form—CO—(CH₂)₃—, —CO—(CH₂)₂—, —CO—CH₂—C(CH₃)₂—CH₂—, —CO—(CH₂)₂—C(CH₃)₂—,—CO—CH₂—CH(CH₃)—CH₂—, —CO—O—CH(CH₃)—CH₂— and —CO—CH₂—S—CH₂—.

Also, particularly preferred pharmaceutical composition of thisinvention are those of the formula (I), wherein R¹ is hydrogen, methylor methoxyethyl; R² is methyl, ethyl, monofluoromethyl, difluoromethyl,trifluoromethyl, phenyl, n-propyl, isopropyl, n-bytyl, isobutyl,methoxymethyl, nitrophenyl, hydroxymethyl or pyridyl; R³ is acetyl,propanoyl, pentanoyl, ethoxycarbonyl, methoxycarbonyl, formyl,methanesulfonyl, hydroxyethyl, hydroxymethyl, benzyloxycarbonyl,allyloxycarbonyl, carboxyl, methylethoxycarbonyl,1,1-dimethylethoxycarbonyl, propoxycarbonyl, butoxycarbonyl ormethoxyethoxycarbonyl; R² and R³ are at the 4 and 3 positions of thepyrrole ring, respectively; R⁴ is methyl, phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, naphthyl, pyridyl, quinolyl, thienyl,phenyl, hydrogen, morpholino, 1-piperidinyl, (1-phenyl)-4-piperazinyl or(2-pyridyl)-4-piperazinyl; and R⁵ is hydrogen.

Preferred individual compounds of this pharmaceutical composition ofthis invention are:

3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole;

3-acetyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole;

3-acetyl-2,5-di(4-pyridyl)-4-trifluoromethyl-1H-pyrrole;

3-methoxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole;

3-acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole;

3-acetyl-4-methyl-2-phenyl-5-(4-pyridyl)-1H-pyrrole;

3-methyl-4-oxo-2-(4-pyridyl)4,5,6,7-tetrahydro-1H-indole;

3-acetyl-2-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-acetyl-2-(2-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

4-Oxo-2-(4-pyridyl)-3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole;

3,6-Dimethyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole;

4-Oxo-2-(4-pyridyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole;

3-Acetyl-2-{(4-methoxycarbonyl)phenyl}-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-4-methyl-2-(1-piperidinyl)-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-4-methyl-2-(4-phenylpiperazin-1-yl)-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-2-(3-chloro-4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-2-(4-chlorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole;

3-Acetyl-2-(4-methoxyphenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole; and

3-Acetyl-4-methyl-2-(4-morpholino)-5-(4-pyridyl)-1H-pyrrole.

GENERAL SYNTHESIS

The compounds of this invention can be prepared by a variety ofsynthetic routes. Representative procedures are outlined as follows.

1. Synthesis of Pyridylpyrroles by Palladium Catalyzed Cross Coupling

The compounds of formula (I) can be prepared by using the method ofStille or Suzuki (for example, Snieckus V. et al., J. Org. Chem., 1995,60, 292, Stille, J. K. Angew. Chem. Int. Ed. Engl., 1986, 25, 508,Mitchell, M. B. et al., Tetrahedron Lett., 1991, 32, 2273, Matteson, D.S., Tetrahedron, 1989, 45, 1859).

(wherein R is an organometallic group such as trialkylstannyl,dialkylboronyl, boric acid or zinc halide such as zinc chloride, zincbromide or zinc iodide; R¹, R², R³, R⁴ and R⁵ are as already definedabove; and X is halo such as Cl, Br or I)

As shown in Scheme 1, the pyrrole compounds (I) can be prepared by areaction of compound (1-1) with pyrrolyl halide (1-2), in the presenceof a catalyst, preferably tetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium(II) chloride, in the inert solvent suchas benzene, toluene, xylene, tetrahydrofuran, dioxane,dimethylformamide, preferably dioxane under suitable conditions.

The reaction of trialkyl(4-pyridyl)stannane (1-1) with pyrrolyl halides(1-2) may be carried out in an inert solvent such as benzene, toluene,xylene, tetrahydrofuran, dioxane, dimethylformamide, preferably dioxane,typically in the presence of lithium chloride and a catalyst. Thecatalyst may be selected from those typically employed for the so-calledStille reaction (for example, tetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium(II) chloride). The reaction may be runat a temperature in a range from 20 to 160° C., preferably 60 to 130°C., for 10 minutes to 5 days, usually 30 minutes to 15 hours.

The reaction of dialkyl(4-pyridyl)borane (1-1) with pyrrolyl halides(1-2) may be carried out in an inert solvent such as benzene, toluene,tetrahydrofuran, preferably toluene, typically in the presence of a basesuch as potassium hydroxide, triethylamine, sodium ethoxide, sodiumacetate or quaternary ammonium halide, preferably potassium hydroxide.The catalyst may be selected from those typically employed for theso-called Suzuki reaction (for example,tetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium(II) chloride). The reaction is run at atemperature in the range from 20 to 160° C., preferably 60 to 130° C.for 10 minutes to 5 days, usually 30 minutes to 15 hours.

The reaction of 4-pyridineboronic acid (1-1) with pyrrolyl halides (1-2)may be carried out in a solvent such as benzene, toluene,dimethoxyethane, dimethylformamide, preferably dimethoxyethane,typically in the presence of a base such as potassium hydroxide,triethylamine, sodium bicarbonate, preferably sodium bicarbonate, or acombination of water and above compounds, preferably water anddimethoxyethane. The catalyst may be selected from those typicallyemployed for the so-called Suzuki reaction (for example,tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium(II) chloride, or{bis(diphenylphosphino)butane}palladium(II) chloride). The reaction isrun at a temperature in the range from 20 to 160° C., usually 60 to 130°C. for 10 minutes to 5 days, usually 30 minutes to 15 hours.

The procedures and conditions to carry out these coupling reactions areknown to those in the art, and described in several technicalliteratures. For example, the procedures of Gronowitz, S. et al. andSnieckus, V. et al. for alkylstannanes are described in J. Het. Chem.,1990, 27, 2165, and J. Org. Chem., 1995, 60, 292; the procedure ofTerashima, M. et al. for alkyl boranes, is in Heterocycles, 1984, 22,265 and 2471, and in Chem. Pharm. Bull., 1983, 31, 4573; and theprocedures of Fischer, F. C., Mitchel, M. B. et al. and McKillop, A. etal. for boric acids are in J. Red. Trav. Chim. Pays-Bays, 1965, 84, 439,Tetrahedron Lett., 1991, 32, 2273, and Tetrahedron, 1992,48,8117.

The 4-metalpyridines (1-1) (R=metal) can be prepared according to theprocedure of the above literatures. The requisite pyrrolyl halides (1-2)can be prepared from the corresponding pyrroles by halogenation known inthe art. The pyrroles for halogenation are either commercially availableor can be prepared by using methods known in the art, for example,Hantzsch's method, Feist's method, Knorr's method and Katritzky's method(Tetrahedron, 1995, 51, 13271).

As apparent to one skilled in the art, the compound (I) can be alsoobtained from a reaction of the compound (1-1) wherein R is halo and thecompound (1-2) wherein X is replaced by an organometallic group such asMe₃Sn, Bu₃Sn—, Et₂B—, (HO)₂B— or zinc halide. The replacement of ahalogen atom by the organometallic group can be carried out by thehalogen-metal exchange, followed by a reaction of appropriate reagentssuch as trimethyltin chloride, tributyltin chloride, diethylmethoxyborane or trimethyl borate.

2. Synthetic Methods of 2,5-Diarylpyrroles

The compounds of the formula (Ia) can be prepared by the following novelmethod.

(wherein R¹, R⁵ and m are as defined above; R^(2a) and R^(3a) areindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Ar orAr—C₁₋₄ alkyl; and R⁷ is an electron withdrawing group exemplified byC(O)R^(3a), C(O)OR^(3a), CN or SO₂R^(3a).)

As shown in Scheme 2, the compounds of the formula (Ia) can be preparedfrom a reaction of aldehyde (2-1), 1,3-dione (2-2a) and amine (2-3) inan inert reaction solvent. For example,3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (Ia) (R¹═R⁵═H,R^(2a)=methyl, R⁷=C(O)CH₃) can be efficiently prepared from4-pyridinecarboxaldehyde (2-1) (R₅=H) and 2,4-pentanedione (2-2a)(R^(2a)═R^(3a)=methyl) in the presence of ammonia (2-3) (R¹=H) in onestep.

This reaction may be carried out in a reaction inert solvent, forexample, ethanol, methanol, toluene, xylene, tetrahydrofuran, methylenechloride, preferably ethanol. However, a solvent is not alwaysnecessary. The novel reactions of this pyrrole synthesis generallyproceed at a temperature in the range from −20 to 250° C., preferably 0to 150° C., more preferably 40 to 110° C. for 10 minutes to 3 days,usually 30 minutes to 15 hours.

The analogs of the compounds (Ia) with a variety of functional groups,such as alkylcarboxy, cyano or sulfonyl, instead of carbonyl, can besynthesized by the use of β-ketoesters (2-2b), β-ketonitriles (2-2c),β-ketosulfones (2-2d) or their equivalents of 1,3-diones instead of the1,3-diones (2-2a) in the above reaction.

As the aldehydes (2-1), quinolinecarboxaldehydes (two of R⁵ are attachedto adjacent carbon atoms on the pyridine ring to complete a fusedbenzene ring) can be also used in this reaction, instead of4-pyridinecarboxaldehyde, to afford 2,5-diquinolylpyrrole compounds.Also, 2,5-diarylpyrroles having different aryl rings at the 2 and5-positions (Ia) can be prepared by the reaction of a mixture of twokinds of arylaldehydes (2-1) with the 1,3-dione (2-2a) or theirequivalent ((2-2b)-(2-2d)) and the amine (2-3). For example,2-pyridyl-5-quinolylpyrroles can be prepared by a reaction of a mixtureof 4-pyridinecarboxaldehyde (2-1) and 4-quinolinecarboxaldehyde (2-1),1,3-dione (2-2a) or their equivalent ((2-2b)-(2-2d)) and amine (2-3). Asshown in Scheme 2b,3-acetyl-4-methyl-2-(4-pyridyl)-5-(4-quinolyl)-1H-pyrrole can beefficiently prepared from 4-pyridinecarboxaldehyde,4-quinolinecarboxaldehyde, 2,4-pentanedione and anmonia in one step.

As amines (2-3), the other ammonia source such as ammonium acetate canbe used in this reaction. By the use of substituted amines (2-3)(R¹=alkyl, aryl) such as alkylamines or arylamine in the above reactioncan give the corresponding 1-substituted pyrroles.

In addition, the functional groups at the 1-, 3- or 4-position of thepyrroles prepared above can be converted to a variety of functionalgroups by the methods known to one skilled in the art.

3. Synthesis of Pyridylpyrroles by Cycloaddition Reaction

The compounds of formula (Ib) or (Ic) can be also prepared by [3+2]cycloaddition as described in Scheme 3.

(wherein Bt is benztriazole)

In Scheme 3, the compounds of the formula (Ib or Ic) can be prepared by[3+2] cycloaddition of thioamidates ((3-2) or (3-4)) and α,β-unsaturatedketones (Michael acceptor) (3-3). This reaction can be carried out in aninert solvent, such as tetrahydrofuran or dimethylformamide, in thepresence of base, preferably sodium hydride. This reaction can becarried out at a temperature in a range from −20 to 150° C., preferably0 to 100° C., for 10 minutes to 3 days, usually 3 minutes to 15 hours.The reaction procedures and conditions are described in, for example,Katritzky A. R. et al., Tetrahedron, 1995, 51, 13271.

Thioamides (3-1) can be readily obtained by Mannich condensation ofsubstituted isonicotinoylthioamide, aldehyde and benztriazole accordingto the literature procedure. Treatment of the thioamides (3-1) with oneequivalent of base such as butyllithium or sodium hydride, followed by areaction with alkyliodide gives thioimidates (3-2). This reaction may becarried out in a reaction inert solvent, for example, tetrahydrofuran,diethylether or methylene chloride, preferably tetrahydrofuran at atemperature in the range from −100 to 50° C., preferably −78 to 20° C.for 10 minutes to 2 days, usually 30 minutes to 3 hours.

In addition, the thioimidates (3-2) can also be alkylated at theα-position leading to the compound (3-4).

Alternatively, the compounds of formula (I) can be also prepared by avariety of methods known in the art, such as Knorr's method, Feist'smethod, and Hantzsch's method.

4. Synthesis of Pyridylpyrroles

The compounds of formula (I) can be also prepared from (4-1) by usingthe method of Stille or Suzuki or by nucleophilic substitution asdescribed in Scheme 4.

(wherein R¹, R², R³, R⁴, and R⁵ are as already defined above; and X ishalo such as Cl, Br, or I) The pyrrolyl halides (4-1) can be preparedfrom the corresponding pyrroles by halogenation known in the art.

The compounds of formula (I) can be prepared by a reaction of compound(4-1) with an appropriate organometallic reagent such astrialkylstannyl, dialkylboronyl, boric acid, in the presence of acatalyst, preferably tetrakis(triphenylphosphine)palladium orbis(triphenylphosphine)palladium(II) chloride, in the inert solvent suchas benzene, toluene, xylene, tetrahydrofuran, dioxane,dimethylformamide, preferably dioxane under suitable conditions.

For example, the reaction of phenylboronic acid with compound (4-1) maybe carried out in a solvent such as benzene, toluene, dimethoxyethane,dimethylformamide, preferably dimethoxyethane, typically in the presenceof a base such as potassium hydroxide, triethylamine, sodiumbicarbonate, preferably sodium bicarbonate, or a combination of waterand above compounds, preferably water and dimethoxyethane. The catalystmay be selected from those typically employed for the so-called Suzukireaction (for example, tetrakis(triphenylphosphine)palladium,bis(triphenylphosphine)palladium(II) chloride, or{bis(diphenylphosphino)butane}palladium(II) chloride). The reaction isrun at a temperature in the range from 20 to 160° C., usually 60 to 130°C. for 10 minutes to 5 days, usually 30 minutes to 15 hours. Theprocedures and conditions to carry out these coupling reactions areknown to those in the art.

The compounds of formula (I) can be prepared by a reaction of compound(4-1) with an appropriate alkylamine or cyclic amine such as piperidine,piperazine, or morpholine, without solvent. This reaction proceeds at atemperature in the range from 20 to 250° C., preferably 80 to 150° C.for 10 minutes to 3 days, usually 30 minutes to 15 hours. This reactionmay also be carried out in the presence of a catalyst, preferablytetrakis(triphenylphosphine)palladium orbis(tri-o-tolylphosphine)palladium(II) chloride, in the inert solventsuch as benzene, toluene, xylene, tetrahydrofuran, dioxane,dimethylformamide, preferably dioxane under suitable conditions. Theprocedures and conditions to carry out these coupling reactions areknown to those in the art. (for example, Buchwald, S. L. et al., Angew.Chem. Int. Ed. Engl., 1995, 34, 1348.)

As the pyridylpyrrole compounds of this invention may possess at leastone asymmetric center, they are capable of occurring in variousstereoisomeric forms or configurations. Hence, the compounds can existin separated (+)- and (−)-optically active forms, as well as in racemicor (±)-mixtures thereof The present invention includes all such formswithin its scope. Individual isomers can be obtained by known methods,such as optically selective reaction or chromatographic separation inthe preparation of the final product or its intermediate.

Insofar as the pyridylpyrrole compounds of this invention are basiccompounds, they are capable of forming a wide variety of different saltswith various inorganic and organic acids.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the aforementioned pyridylpyrrole base compounds ofthis invention of formula (I) are those which form non-toxic acidaddition salts, i.e., salts containing pharmaceutically acceptableanions, such as chloride, bromide, iodide, nitrate, sulfate orbisulfate, phosphate or acid phosphate, acetate, lactate, citrate oracid citrate, tartrate or bi-tartrate, succinate, maleate, fu marate,gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1.1′-methylene-bis-(2-hydroxy-3-naphthoate))salts.

The pharmaceutically acceptable salts of the present invention alsoinclude alkali or alkaline earth metal salts such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. Quaternary salts obtained from compounds of the inventionand C₁₋₄ alkyl halide are also included. The other pharmaceuticallyacceptable salts which can be used in the present invention aredescribed in J. Pharmacelitical Scienices, 1977, 66, 1-19.

These salts can be prepared by conventional procedures.

METHOD OF TREATMENT

The compounds (I) of this invention prepared as mentioned above inhibitinflammatory stimuli-induced cytokines production such as tumor necrosisfactor alpha (TNF-α) and interleukine-1β (IL-1β), and are useful in thetreatment or alleviation of various cytokine-mediated diseases such asasthma, arthritis, inflammatory bowel disease (IBD), sepsis, septicshock, rhinitis, inflammation of organs (e.g. hepatitis), AIDS andvarious inflammatory diseases. Furthermore, the compounds of thisinvention inhibit inflammatory stimuli-induced synthesis of proteinsthat regulate adhesion of leukocytes to other leukocytes and to othercell types and have potential use in the treatment of inflammatory andimmune disorders such as arthritis and IBD; cardiovascular diseases,psoriasis and transplant rejection.

The pyridylpyrrole compounds of formula (I) of this invention can beadministered via either the oral, parenteral or topical routes tomammals. In general, these compounds are most desirably administered tohumans in doses ranging from 0.3 mg to 750 mg per day, preferably from10 mg to 500 mg per day, although variations will necessarily occurdepending upon the weight and condition of the subject being treated,the disease state being treated and the particular route ofadministration chosen. However, for example, a dosage level that is inthe range of from 0.06 mg to 2 mg per kg of body weight per day is mostdesirably employed for the treatment of inflammation.

The compounds (I) of the present invention may be administered alone orin combination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated, and such administrationcan be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover,oralpharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging 5% to 70% by weight, preferably 10% to 50% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate,dipotassium phosphate and glycine may be employed along with variousdisintegrants such as starch and preferably corn, potato or tapiocastarch, alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatine capsules; preferred materials in this connectionalso include lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH>8) if necessary and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well-known to those skilled in theart. Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, ointments and the like, in accordance with standardpharmaceutical practice.

The ability of the compounds of the formula (I) to inhibit TNFαbiosynthesis and CAMs expression may be demonstrated in vitro by thefollowing procedures.

METHOD FOR DETERMINING THE INHIBITION OF TNFα BIOSYNTHESIS AND CAMsEXPRESSION

1. Cells and Cell Culture:

L929 cells are grown in minimum essential medium (MEM) (Gibco BRL NY)supplemented with 10% FCS, 50 U/mL penicillin and 50 μg/mL streptomycin.Human umbilical vein endothelial cells (HUVECs) are obtained fromMorinaga and grown in endothelial growth medium (E-GM UV, Kurabou,Japan) supplemented with 10% fetal calf serum (FCS, Biowhitakker,Walkersyille, Md.), 10 ng/mL EGF, 1 μg/mL hydrocortisone, and 1:100dilution of bovine brain extract (Kurabou, Japan) in 5% CO₂ at 37° C. Ahuman promyelocytic cell line, HL-60 cells are grown in RPMI-1640(Nissui Seiyaku, Tokyo, Japan) supplemented with 10% FCS plus penicillin(50 U/mL) and streptomycin (50 μg/mL).

The ability of the compounds of the formula (I) to inhibit TNFαbiosynthesis may be demonstrated in vitro by the following procedure 2.

2. TNFα Production:

Human peripheral blood mononuclear cells (HPBMNC) are isolated fromheparinized human whole blood by Ficoll-Paque (Pharmacia, Sweden)density centrifugation, washed with Ca—Mg free phosphate-buffered saline(PBS, Nissui Seiyaku, Tokyo, Japan), suspended in RPMI 1640 containing10% FCS and plated into 48 well plates (Falcon, Becton Dickinson, N.J.)at 2×10⁶ cells/well. Monocytes (HBMo) are allowed to adhere to the plateby incubating at 37° C. for 1 hour, then the supernatant is aspiratedand refilled with fresh RPMI-1640 medium containing 1% FCS.

Test compounds are prepared as 100 mM dimethyl sulfoxide (Me₂SO) stocksolutions and diluted with media to obtain final testing concentrations.HMo are incubated at 37° C. for 4 hours in the presence of LPS (E. coli.055:B5, Difco, Mich.) of 10 μg/mL with the test compounds in dose rangesof 0.1 μM˜100 μM. The assay is run in a volume of 200 μL/well.Supernatants are subjected to quantitation of TNFα by an L929 cellcytotoxicity assay. On the day of the experiment, L929 cells aredetached by trypsin treatment, washed with MEM and resuspended with 1%FCS-containing MEM. L929 cells (8×10⁵ cells/well) in a volume of 50 μLare plated into flat-bottomed 96 well plate (Corning, N.Y.) andincubated with 50 μL of serially diluted supernatants in the presence offinally 0.5 μg/mL of actinomycin D (Wako, Japan) at 37° C. in 5% CO₂ for18 hours. After incubation, the culture medium is removed and viablecells are stained with 0.2% crystal violet dissolved in 20% ethanol. Thecells are washed with tapping water and air-dried at room temperature.Resulting crystal violet is dissolved in 100 μl of 100% methanol and theoptical density is determined at 595 nm on a BIO—RAD plate reader(Richmond, Calif.). The concentration of TNFα is regressed by humanrecombinant TNFα (Wako, Japan) set as a standard. Percent inhibition isdetermined by comparing the absorbance of vehicle treated cells withdrug treated cells. Linear regression analysis of the means of theinhibition values are used to determine the IC₅₀s.

Some compounds prepared in the Working Examples as described below weretested by this method, and showed an IC₅₀ value of 100 nM to 10 μM withrespect to inhibition of TNFα biosynthesis.

The ability of the compounds of the formula (I) to inhibit CAMsexpression may be demonstrated in vitro by the following procedures 3and 4.

3. Cell ELISA:

Test compounds are diluted with media to obtain final testingconcentrations. HUVECs (1.2×10⁴/well) grown in flat-bottomed, 96 well,culture plates (Corning, N.Y.) are stimulated with human TNFα (3 U/mL,Wako, Tokyo, Japan) in the presence or absence of test compounds. Cellsare incubated for 6 hours, then washed in PBS, fixed in 4%paraformaldehyde for 15 minutes, washed and stored for 1-3 days at 4° C.in PBS.

Adhesion molecules are detected using ELISA. Cells are incubated with aprimary antibody to either ICAM-1 (0.5 μg/mL) (BA#3, R&D Systems) orE-selectin (0.5 μg/mL) (BBA#1, R&D Systems). Anti-mouse Ig,peroxidase-linked species-specific F(ab′)₂ fragment (from sheep)(Amersham; 1:2500 dilution) is used as the second antibody, followed bythe addition of peroxidase substrate, o-phenylenediamine. The absorbanceof each well is read with a Bio-Rad plate reader at 490 nm, and thebackground at 655 nm is subtracted. The absorbance of nonstimulatedHUVECs is subtracted from the absorbance values of TNFα- stimulatedcells. Percent inhibition is determined by comparing the absorbance ofvehicle treated cells with drug treated cells. Linear regressionanalysis of the means of the inhibition values are used to determine theIC₅₀s.

Some compounds prepared in the Working Examples as described below weretested by this method, and showed an IC₅₀ value of 50 nM to 10 μM withrespect to inhibition of the CAMs expression.

4. Cell Adhesion Assay:

BL-60 cells are induced to differentiate into granulocyte-like cells by1.25% Me₂SO in RPMI-1640 supplemented with 10% heat-inactivated FCS for5-6 days. Then cells are incubated with 300 μM of fluorescent dye,5(6)-carboxyl fluorescein diacetate, for 30 minutes at 37° C. and washedthree times with Hank's solution. HUVECs (1.2×10⁴/well) grown in 96 wellplates are simultaneously treated with the test compounds which arediluted with media to obtain final testing concentrations and 30 U/mLTNFα for 6 hours. Labeled cells (5×10⁵/well) are added to TNFα-stimulated HUVECs in a final volume of 0.1 mL gently washing four timeswith warm Hank's solution, and remaining cells are lysed with 1% NonidetP-40. The number of adherent cells are determined by measuring thefluorescence intensity using a Fluoroscan II (excitation at 485 nm andemission at 538 nm). Percent inhibition is determined by comparing thefluorescence intensity of vehicle treated cells with drug treated cells.Linear regression analysis of the means of the inhibition values areused to determine the IC₅₀s.

Some compounds prepared in the Working Examples as described below weretested by this method, and showed an IC₅₀ value of 50 nM to 10 μM withrespect to inhibition of the adhesion of HL-60 to HUVECs stimulated byTNFα.

EXAMPLES

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples. Melting points were taken with aBuchi micro melting point apparatus and uncorrected. Mass spectra wererecorded on a JEOL JMS-AM120 or API-III (Perkin-Elmer SCIEX)triple-quadrupole mass analyzer. Infrared Ray absorption spectra (IR)were measured by a Shimazu infrared spectrometer (IR-470). ¹H and ¹³Cnuclear magnetic resonance spectra (NMR) were measured in CDCl₃ by aJEOL NMR spectrometer (JNM-GX270, 270 MHz) unless otherwise indicatedand peak positions are expressed in parts per million (ppm) downfieldfrom tetramethylsilane. The peak shapes are denoted as follows: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.Coupling constants (J) are recorded in hertz. The followingabbreviations are used: MeOH for methanol, EtOH for ethanol, DMSO fordimethylsulfoxide, DMF for N,N-dimethylformamide, THF fortetrahydrofuran, HCl for hydrogen chloride or CH₂Cl₂ fordichloromethane.

Example 1 3-Acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

To a stirred solution of 4-pyridinecarboxaldehyde (14.8 g ; 0.138 mol)and 2,4-pentanedione (12.5 g; 0.125 mol) in EtOH (15 mL) was added 25%aqueous ammonia solution (8 mL) at room temperature. The resultingmixture was stirred for 15 minutes at room temperature, and then heatedat reflux temperature for 3 hours. After cooling, the obtainedprecipitates were collected by filtration to give 18.7 g.Recrystallization from EtOH provided the title compound (14.1 g, 41%yield) as a colorless solid. X-ray analysis (recrystallized fromEtOH/H₂O) indicated the title structure.

mp: 237-239.5° C.; ¹H-NMR (DMSO-d₆) δ 12.00 (br. s, 1H), 8.66 (dd,J=4.4, 1.9 Hz, 2H), 8.62 (dd, J=4.4, 1.9Hz, 2H), 7.54 (dt, J=4.4, 1.9Hz,4H), 2.35 (s, 3H), 2.18 (s, 3H); MS (EI) m/z 277 (M⁺); Anal. Calcd forC₁₇H₁₅N₃O: C, 73.63; H, 5.45; N, 15.15. Found: C, 73.44; H, 5.39; N,15.20.

Example 2 3-Acetyl-4-methyl-2.5di(4-pyridyl)-1H-pyrrole DihydrochlorideMonohydrate

3-Acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole was dissolved in 10%HCl-MeOH. After removal of volatiles, the crude salt was recrystallizedfrom EtOH to give the title compound.

mp: 238-241° C. (Recryst. from EtOH); ¹H-NMR (DMSO-d₆) δ 12.0 (s, 1H),8.66 (dd, J=4.4, 1.9 Hz, 2H), 8.62 (dd, J=4.4, 1.9 Hz, 2H), 7.55 (dd,J=4.4, 1.5 Hz, 2H), 7.53 (dd, J=4.4, 1.5 Hz, 2H), 2.35 (s, 3H), 2.18 (s,3H); MS (EI) m/z 278 (M+H); Anal. Calcd for C₁₇H₁₅N₃O 2HCl H₂O: C,55.45; H, 5.20; N, 11.41; Cl, 19.25. Found: C, 55.21; H, 5.17; N, 11.48;Cl, 19.19.

The compounds from Example 3 to 7 were prepared according to theprocedure of Example 1 using the corresponding 1,3-diones instead of2,4-pentanedione.

Example 3 4-Ethyl-3-propanoyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 209-211° C.; IR (KBr) ν 3500, 1660, 1600, 1460, 1430, 1420, 1220,1000, 940, 840, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.90 (br. s, 1H), 8.66(dd, J=4.4 Hz, 1.5 Hz, 2H), 8.62 (dd, J=4.4 Hz, 1.5 Hz, 2H), 7.53 (dd,J=4.4 Hz, 1.5 Hz, 2H), 7.47 (dd, J=4.4 Hz, 1.5 Hz, 2H), 2.71 (q, J=7.3Hz, 2H), 2.41 (q, J=7.3 Hz, 2H), 1.16 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.3Hz, 3H); Anal. Calcd. for C₁₉H₁₉N₃O: C, 74.73; H, 6.27; N. 13.76. Found:C, 74.68; H, 6.35; N, 13.69.

Example 4 3-Acetyl-2,5-di(4-pyridyl)-4-trifluoromethyl-1H-pyrrole

mp: 250-255° C. (Recryst. from ethyl acetate) ¹H-NMR: (DMSO-d₆) δ 12.50(br. s, 1H), 8.72 (dd, J=4.4 Hz, 1.5 Hz, 2H), 8.68 (dd, J=4.4 Hz, 1.8Hz, 2H), 7.88-7.83 (m, 2H), 7.67-7.61 (m, 2H), 2.32 (s, 3H); Anal.Calcd. for C₁₇H₁₂N₃OF₃: C, 61.63; H, 3.65; N, 12.68. Found: C, 61.79; H,3.57; N, 12.48.

Example 5 4-Methyl-3-propanoyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 237-238° C.; IR (KBr) ν 1670, 1600, 1460, 1430, 1410, 1320, 1000,820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.90 (br. s, 1H), 8.66-8.60 (m, 4H),7.58-7.46 (m, 4H), 2.49-2.43 (m, 2H), 2.31 (s, 3H), 0.97 (t, J=7.3 Hz,3H); MS (EI) m/z 291 (M⁺); Anal. Calcd. for C₁₈H₁₇N₃O 1.4H₂O: C, 68.29;H, 6.30; N, 13.27. Found: C, 67.93; H, 5.90; N, 12.97.

Example 6 4-Methyl-2,5-di(4-pyridyl)-3-pentanoyl-1H-pyrrole

mp: 88-89° C. (Recryst. from ethyl acetate-hexane); IR (KBr) ν 3400,1660,1600, 1460, 1440, 1320, 1000, 830 cm⁻¹; ¹H-NMR: (DMSO-d₆) δ 11.95(br. s, 1H), 8.65 (d, J=5.9 Hz, 2H), 8.61 (d, J=5.5 Hz, 2H), 7.55 (d,J=5.9 Hz, 2H), 7.48 (d, J=5.5 Hz, 2H), 2.50-2.41 (m, 2H), 2.30 (s, 3H),1.47 (q, J=7.3 Hz, 2H), 1.22-1.08 (m, 2H), 0.75 (t, J=7.3 Hz, 3H); Anal.Calcd. for C₂₀H₂₁N₃O 1.25H₂O: C, 70.26; H, 6.93; N, 12.29. Found: C,70.15; H, 6.76; N, 12.40.

Example 7 3-Acetyl-4-phenyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 208-210° C.; ¹H-NMR (DMSO-d₆) δ 12.30 (br. s, 1H), 8.75-8.60 (m,2H), 8.45-8.36 (m, 2H), 7.70-7.20 (m, 9H), 1.88 (s, 3H).

The compound of Example 8 was prepared according to the procedure ofExample 1 using 4-quinolinecarboxaldehyde instead of4-pyridinecarboxaldehyde.

Example 8 3-Acetyl-4-methyl-2,5-di(4-quinolyl)-1H-pyrrole

mp >260° C. (recryst. from ethyl acetate-hexane); ¹H-NMR: (CDCl₃) δ10.24 (s, 1H), 8.74 (dd, J=4.0, 2.5 Hz, 2H), 8.03-7.83 (m, 4H),7.73-7.50 (m, 4H), 7.39 (d, J=4.4 Hz, 1H), 7.33 (d, J=4.4 Hz, 1H), 2.27(s, 3H), 1.87 (s, 3H); Anal. Calcd. for C₂₅H₁₉N₃O: C, 79.55; H, 5.07; N,11.13. Found: C, 79.15; H, 5.08; N, 10.99.

Example 9 3-Acetyl-4-methyl-2-(4-pyridyl)-5-(4-quinolyl)-1H-pyrrole

To a stirred solution of 4-quinolinecarboxaldehyde (2.3 g; 14.8 mmol),4-pyridinecarboxaldehyde (1.6 g ; 14.8 mmol) in EtOH (40 mL) was added2,4-pentanedione (2 g; 20 mmol) and 25% aqueous ammonia solution (8 ml)at room temperature. The mixture was heated at reflux temperature for 18hours. After cooling, volatiles were removed by evaporation.Chromatographic purification of the residue on silica gel eluting withCH₂Cl₂—EtOH (20:1→8:1) provided 1.1 g, which was recrystallized fromEtOH to afford the title compound (0.82 g, 17% yield) as a pale yellowsolid.

mp: 237-239° C.; ¹H-NMR (CDCl₃) δ 10.84 (s, 1H), 8.70 (d, J=4.4 Hz, 1H),8.39 (d, J=5.1 Hz, 2H), 7.95 (d, J=8.4 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H),7.64 (t, J=7.0 Hz, 1H), 7.52 (t, J=7.0 Hz, 1H), 7.40 (d, J=5.9 Hz, 2H),7.26 (d, J=4.4 Hz, 1H), 2.31 (s, 3H), 2.16 (s, 3H); Anal. Calcd. forC₂₁H₁₇N₃O: C, 77.04; H, 5.23; N, 12.83. Found: C, 77.26; H, 5.23; N,12.77.

Example 10 3-Ethoxycarbonyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole

To a stirred solution of ethyl propionylacetate (2.03 g, 13.7 mmol) inEtOH (10 mL) was added 4-pyridinecarboxaldehyde (2.92 g, 27.3 mmol) and25% aqueous ammonia solution (4 mL, 58.8 mmol) at room temperature. Themixture was heated at reflux temperature for 7 hours. After cooling, theresulting precipitates were collected by filtration, and washed withethyl acetate to give the title product (1.44 g, 37% yield) as a solid.

mp: 212-215° C.; ¹H-NMR (DMSO-d₆) δ 8 11.99 (br. s, 1H), 8.62 (dt, J=4.4Hz, 1.8 Hz, 4H), 7.53 (dt,J=4.4 Hz, 1.8 Hz, 4H), 4.14 (q, J=7.0 Hz, 2H),2.81 (q, J=7.3 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H), 1.13 (t, J=7.0 Hz, 3H);IR (KBr) ν 3000, 1700, 1600, 1580, 1460, 1280, 1170,1140, 1100,820cm⁻¹;Anal. Calcd. for C₁₉H₁₉N₃O₂: C, 71.01; H, 5.96; N, 13.07. Found: C,71.05; H, 5.95; N, 12.98.

The compounds from Example 11 to 25 were prepared according to theprocedure of Example 10 using the corresponding β-ketoesters instead ofethyl propionylacetate.

Example 11 3-Ethoxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 206-208° C.; IR (KBr) ν 1700, 1600, 1580, 1470, 1260, 1140, 1080,820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.01 (br. s, 1H), 8.65-8.55 (m, 4H),7.57-7.46 (m, 4H), 4.14 (q, J=7.0 Hz, 2H), 2.40 (s, 3H), 1.13 (t, J=7.0Hz, 3H); MS (EI) m/z 307 (M⁺); Anal. Calcd. for C₁₈H₁₇N₃O₂: C, 70.34; H,5.57; N, 13.64. Found: C, 70.18; H, 5.60; N, 13.45.

Example 12 3-Methoxycarbonyl-4-methyl-2,5-di(4-pyridyl-1H-pyrrole

mp: 245-247° C. (Recryst. from ethyl acetate-EtOH); IR (KBr) ν 1700,1600, 1460, 1360, 1260, 1080, 1000, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.03(br. s, 1H), 8.62 (d, J=5.8 Hz, 4H), 7.56 (d, J=5.8 Hz, 2H), 7.53 (d,J=5.8 Hz, 2H), 3.66 (s, 3H), 2.39 (s, 3H); Anal. Calcd. for C₁₇H₁₅N₃O₂:C, 69.61; H, 5.15; N 14,33. Found: C, 69.93; H, 5.09; N, 14.38.

Example 13 3-Benzyloxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 204-205° C. (Recryst. from water-EtOH); IR (KBr) ν 3400, 1700, 1600,1550, 1250, 1150, 1060, 820, 690, 660 cm⁻¹; ¹H-NMR (CDCl₃) δ 9.51 (br.s, 1H), 8.59-8.46 (m, 4H), 7.36-7.22 (m, 9H), 5.23 (s, 2H), 2.50 (s,3H); MS (EI) m/z 369 (M⁺); Anal. Calcd for C₂₃H₁₉N₃O₂₂O H₂O: C, 71.30;H, 5.46; N, 10.85. Found: C, 71.36; H, 5.33; N, 10.90.

Example 14 3-Allyloxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 224-224.5° C. (Recryst. from water-EtOH); IR (KBr) ν 3450, 1690,1600, 1580, 1460, 1270, 1140, 1080, 990, 830 cm⁻¹; ¹H-NMR (DMSO-d₆) δ12.05 (br. s, 1H), 8.63-8.59 (m, 4H), 7.57-7.52 (m, 4H), 5.95-5.80 (m,1H), 5.18-5.16 (m, 1H), 5.12 (t, J=1.6 Hz, 1H), 4.63 (dt, J=1.4, 1.4 and5.5 Hz, 2H), 2.41 (s, 3H); MS (EI) m/z, 319 (M⁺); Anal. Calcd forC₁₉H₁₇N₃O₂: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.61; H, 5.30; N,13.13.

Example 154-Methyl-3-(1-methylethoxy)carbonyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 218-221° C. (Recryst. from water-EtOH); I R(KBr) ν 3300, 1700, 1600,1590, 1470, 1280, 1150, 1080, 1000,830cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.99(br. s, 1H), 8.62 (d, J=6.2 Hz, 4H), 7.57-7.52 (m, 4H), 5.06-4.97 (m,IfH), 2.39 (s, 3H), 1.14 (d, J=6.2 Hz, 6H); Anal. Calcd forC₁₉H₁₉N₃O₂.0.65H₂O: C, 68.51; H, 6.14; N, 12.62. Found: C, 68.15; H,6.18; N, 12.97; MS (EI) m/z, 321 (M⁺).

Example 164-Methyl-3-(1,1-dimethylethoxy)carbonyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 265-267° C. (Recryst. from water-EtOH); IR (KBr) ν 3450, 1690, 1610,1580, 1340, 1270, 1150, 1080, 1000, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.93(br. s, 1H), 8.65-8.58 (m, 4H), 7.56-7.49 (m, 4H), 2.38 (s, 3H), 1.36(s, 9H); MS (EI) m/z, 335 (M⁺); Anal. Calcd for C₂₀H₂₁N₃O₂: C, 71.62; H,6.31; N, 12.53. Found: C, 71.54; H, 6.31; N, 12.54.

Example 17 4-Methyl-3-propoxycarbonyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 215-218° C. (Recryst. from water-EtOH); IR (KBr) ν 3400, 1700, 1600,1590, 1460, 1280, 1140, 1080, 1000, 830 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.02(br. s, 1H), 8.61 (d, J=5.9 Hz, 4H), 7.56-7.47 (m, 4H), 4.05 (t, J=6.4Hz, 2H), 2.40 (s, 3H), 1.59-1.45 (m, 2H), 0.75 (t, J=7.3 Hz, 3H). MS(EI) m/z, 321 (M⁺); Anal. Calcd for C₁₉H₁₉N₃O₂0.8H₂O: C, 67.96; H, 6.18;N, 12.51. Found: C, 67.84; H, 6.16; N, 12.60.

Example 18 3-Ethoxycarbonyl-4-phenyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 99-100° C. (Recryst. from ethyl acetate-hexane) IR (KBr) ν 3400,1710, 1600, 1590, 1460, 1280, 1150, 1100, 1000,830 cm⁻¹; ¹H-NMR (CDCl₃)δ 9.92 (br. s, 1H), 8.63-8.57 (m, 2H), 8.38-8.33 (m, 2H), 7.58-7.01 (m,9H), 4.02 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H); MS (EI) m/z, 369(M⁺); Anal. Calcd for C₂₃H₁₉N₃O₂ 1.2H₂O: C, 70.65; H, 5.52; N, 10.75.Found: C, 70.51; H, 5.34; N, 11.13.

Example 19 3-Butoxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 182-186° C. (Recryst. from ethanol-hexane) IR (KBr) ν 3400, 1700,1600, 1580, 1460, 1260, 1140, 1080, 1000, 830 cm⁻¹; ¹H-NMR (MSOd₆) δ12.01 (br. s, 1H), 8.61 (d, J=5.9 Hz, 4H), 7.57-7.53 (m, 4H), 4.08 (t,J=6.4 Hz, 2H), 2.40 (s, 3H), 1.52-1.42 (m, 2H), 1.22-1.08 (m, 2H), 0.80(t, J=7.3 Hz, 3H); MS (EI) m/z, 335 (M⁺); Anal. Calcd for C₂₀H₂₁N₃O₂: C,71.62; H, 6.31; N, 12.53. Found: C, 71.65; H, 6.39; N, 12.66.

Example 203-(2-Methoxyethoxy)carbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 174-177° C. (Recryst. from water-EtOH); IR (KBr) ν 3450, 1700, 1600,1580, 1470, 1260, 1080, 830 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.02 (br. s, 1H),8.63-8.60 (m, 4H), 7.57-7.54 (m, 4H), 4.23 (t, J=4.6 Hz, 2H), 3.47 (t,J=4.6 Hz, 2H), 3.19 (s, 3H), 2.40 (s, 3H); MS (EI) m/z, 337 (M⁺); Anal.Calcd for C₁₉H₁₉N₃O₃ H₂O: C, 64.21; H,5.96; N, 11.82. Found: C, 63.97;H, 5.98; N, 11.80.

Example 21 3-Ethoxycarbonyl-4-propyl-2,9di(4-pyridyl)-1H-pyrrole

mp: 209-211° C.; IR (KBr) ν 3500, 1690, 1600, 1580, 1460, 1270, 1140,820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.99 (br. s, 1H), 8.65-8.58 (m, 4H),7.56-7.48 (m, 4H), 4.13 (q, J=7.3 Hz, 2H), 2.82-2.71 (m, 2H), 1.64-1.50(m, 2H),1.13 (t, J=7.3 Hz, 0.92 (t, J=7.3 Hz, 3H); Anal. Calcd. forC₂₀H₂₁N₃O₂: C, 71.62 H, 6.31; N, 12.53. Found: C, 71.66; H, 6.34; N,12.40.

Example 223-Ethoxycarbonyl-4-(1-methyethyl)-2,5-di(4-pyridyl)-1H-pyrrole

mp: 245-247° C.; IR (KBr) ν 3000, 1700, 1600, 1580, 1460, 1300, 1260,1180, 1140, 1100, 1030, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.90 (br. s, 1H),8.67-8.57 (m, 4H), 7.48-7.44 (m, 4H), 4.15 (q, J=7.0 Hz, 2H), 3.24-3.12(m, 1H), 1.30 (d, J=7.0 Hz, 6H), 1.06 (t, J=7.0 Hz, 3H); Anal. Calcd.for C₂₀H₂₁N₃O: C, 71.62; H, 6.31; N, 12.53. Found: C, 71.32; H, 6.30; N,12.36.

Example 23 3-Ethoxycarbonyl-4-butyl-2,5-di(4-pyridyl-1H-pyrrole

mp: 256-258° C.; IR (KBr) ν 3000, 1700,1600, 1580, 1460, 1280, 1260,1170, 1100, 1070, 820cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.98 (br. s, 1H), 8.61(dt, J=4.8 Hz, 1.5 Hz, 4H), 7.52 (dt, J=4.8 Hz, 1.5 Hz, 4H), 4.14 (dd,J=14.4 Hz, 7.3 Hz, 2H), 2.80-2.76 (m, 2H), 163-1.47 (m, 2H), 1.41-1.27(m, 2H), 1.13 (t, J=7.3 Hz, 3H), 0.89 (t, J=7.3 Hz, 3H); Anal. Calcd.for C₂₁H₂₃N₃O₂: C, 72.18; H, 6.63; N, 12.03. Found: C, 71.85; H, 6.69;N, 11.98.

Example 243-Methoxycarbonyl-4-methoxymethyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 97-99° C.; IR (KBr) ν 3400, 1710, 1600, 1590, 1470, 1260, 1200,1080, 1000, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.28 (br. s, 1H), 8.70-8.60(m, 4H), 7.63 (d, J=4.8 Hz, 2H), 7.55 (d, J=4.8 Hz, 2H), 4.53 (s, 2H),3.68 (s, 3H); 3.34 (s, 3H); Anal. Calcd. for C₁₈H₁₇N₃O₃ 1.0H₂O: C,63.33; H, 5.61; N, 12.31. Found: C, 63.30; H, 5.64; N, 12.20.

Example 253-Ethoxycarbonyl-4-(4-nitrophenyl)-2,5-di(4-pyridyl)-1H-pyrrole

mp: 274-276° C.; IR (KBr) ν 1700, 1600, 1580, 1510, 1470, 1440, 1380,1140, 1100, 930 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.53 (br. s, 1H), 8.67 (d,J=4.8 Hz, 2H), 8.46 (d, J=4.8 Hz, 2H), 8.23 (d, J=4.8 Hz, 2H), 7.65 (d,J=4.8 Hz, 2H), 7.52 (d, J=4.4 Hz, 2H), 7.19 (d, J=4.7 Hz, 2H), 3.94 (q,J=7.3 Hz, 2H), 0.85 (t, J=7.3 Hz, 3H); Anal. Calcd. for C₂₃H₁₈N₄O₄: C,66.66; H, 4.38; N, 13.52. Found: C, 66.39; H, 4.33; N, 13.33.

Example 26 3-Formyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

The titled compound was prepared according to the procedure of Example 1using either trans-4-methoxy-3-buten-2-one or 1,1-dimethoxybutan-3-oneinstead of 2,4-pentanedione.

mp: 278-280° C. (recryst. from EtOH); IR (KBr) ν 1670, 1600, 1590, 1460,1220, 1000, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.31 (br. s, 1H), 9.94 (s,1H), 8.70 (d, J=5.9 Hz, 2H), 8.65 (d, J=5.9 Hz, 2H), 7.68 (d, J=5.9 Hz,2H), 7.60 (d, J=5.9 Hz, 2H), 2.50 (s, 3H); Anal. Calcd. for C₁₆H₁₃N₃O1.0H₂O: C, 68.31; H, 5.37; N, 14.94. Found: C, 68.49; H, 5.35; N, 14.85.

Example 27 3-Metha nesulfonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

The titled compound was prepared according to the procedure of Example 1using methanesulfonyl acetone instead of 2,4-pentanedione.

mp: 232-234° C.; IR (KBr) ν 3350, 1600, 1410, 1290, 1120, 820, 770 cm⁻¹;¹H-NMR (DMSO-d₆) δ 12.34 (br. s, 1H), 8.64 (d, J=4.8 Hz, 4H), 7.57 (dd,J=10.0 Hz, 6.0 Hz, 4H), 3.19 (s, 3H), 2.44 (s, 3H); MS (EI) m/z 313(M⁺);

Example 28 3-Acetyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole

The suspension of sodium hydride (NaH) (60% oil dispersion, 1.78 g, 44.5mmol) in DMSO (15 mL) was heated at 70° C. for 2.5 hours under nitrogen.After cooling, the resulting solution of methylsulfinyl carbanion wasadded to 3-ethoxycarbonyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole (1.43 g,4.45 mmol). The mixture was heated at 70° C. for 1 hour under nitrogen.After cooling, the mixture was diluted with benzene (25 mL) and water (5mL). Zinc (0.87 g, 13.4 mmol) was added to the resulting mixture, andthen heated at reflux temperature for 15 hours. After cooling, water wasadded to the mixturethen extracted with ethyl acetate-EtOH (5:1, 100mL×3). Combined organic layers were washed with brine (50 mL), driedover MgSO₄, and concentrated in vaciio. The crude product was purifiedby flash chromatography eluting with CH₂Cl₂—EtOH (5:1) to give the titleproduct (270 mg, 21% yield) as a colorless solid.

mp: 241-243° C.; ¹H-NMR (DMSO-d₆) δ 11.90 (br. s, 1H), 8.64-8.55 (m,4H), 7.48 (d, J=4.4 Hz, 4H), 2.74-2.66 (m, 2H), 2.07 (s, 3H), 1.20-1.10(m, 3H); IR (KBr) ν 1660, 1600, 1460, 1430, 1410, 1000, 820 cm⁻¹; MS(EI) m/z 291 (M⁺); Anal. Calcd. for C₁₈H₁₇N₃O 0.3H₂O: C, 72.85; H, 5.98;N, 14.16. Found: C, 72.69; H, 5.98; N, 13.81.

The compounds from Example 29 to 32 were prepared according to theprocedure of Example 28 using the corresponding methoxy- orethoxycarbonylpyrroles instead of3-ethoxycarbonyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole.

Example 29 3-Acetyl-4-propyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 111-113° C.; IR (KBr) ν 3400, 1660, 1600, 1460, 1430, 1000, 830,770, 520 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.96 (br. s, 1H), 8.68-8.58 (m, 4H),7.55-7.48 (m, 4H), 2.76-2.64 (m, 2H), 2.12 (s, 3H), 1.64-1.45 (m, 2H),0.92 (t, J=7.3 Hz, 3H).

Example 30 3-Acetyl-4-(1-methyethyl)-2,5-di(4-pyridyl)-1H-pyrrole

mp: 270-275° C. (Recryst. from ethyl acetate); IR (KBr) ν 1670, 1600,1450, 1420, 1350, 1250, 1000, 960, 820, 540 cm⁻; ¹H-NMR (DMSO-d₆) δ11.89 (br. s, 1H), 8.65 (d, J=5.1 Hz, 4H), 7.46 (t, J=4.6 Hz, 4H),3.18-3.07 (m, 1H), 2.16 (s, 3H), 1.26 (d, J=7.0 Hz, 6H); Anal. Calcd.for C₁₉H₁₉N₃O 0.4H₂O: C, 73.01; H, 6.38; N, 13.44. Found: C, 73.23; H,6.25; N, 13.29.

Example 31 3-Acetyl-4-butyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 93-95° C.; IR (KBr) ν 3400, 1660, 1600, 1460, 1430, 1000, 830 cm⁻¹;¹H-NMR (DMSO-d₆) δ 11.95 (br. s, 1H), 8.69-8.57 (m, 4H), 7.55-7.48 (m,4H) 2.78-2.67 (m, 2H), 2.12 (s, 3H), 1.56-1.42 (m, 2H), 1.36-1.24 (m,2H), 0.87 (t, J=7.3 Hz, 3H); Anal. Calcd. for C₂₀H₂₁N₃O 1.3H₂O: C,70.07; H, 6.94; N, 12.26. Found: C, 70.02; H, 6.89;N, 11.94.

Example 32 3-Acetil-4-methoxymethyl-2,5-di(4-pyridyl)-1H-pyrrole

mp: 154-156° C.; IR (KBr) ν 3500, 1660, 1600, 1460, 1430, 1270, 1090,830, 820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 12.21 (br. s, 1H), 8.68-8.62 (m, 4H),7.61-7.52 (m, 4H), 4.44 (s, 2H), 3.33 (s, 3H), 2.28 (s, 3H); Anal.Calcd. for C₁₈H₁₇N₃O₂ 0.5H₂O: C, 68.34; H, 5.73; N, 13.28. Found: C,68.68; H, 5.64; N, 13.18.

Example 33 3-Acetyl-4-hydroxymethyl-2,5-di(4-pyridyl)-1H-pyrrole

3-Acetyl-4-methoxymethyl-2,5-di(4-pyridyl)-1H-pyrrole (0.36 g, 1.17mmol) was dissolved in 10% aqueous HCl solution (14 mL). The mixture washeated at 70° C. for 15 hours. After cooling, the mixture wasneutralized with saturated aqueous sodium bicarbonate solution.Insolubles were filtered off, and the filtrate was extracted with ethylacetate-EtOH (5:1, 200 mL×2). The combined organic layers were washedwith brine (50 mL), dried over MgSO₄, and concentrated ill vaciio. Thecrude product was recrystallized from ethyl acetate to provide the titleproduct (150 mg, 44% yield) as a solid.

mp: 205-207° C.; ¹H-NMR (DMSO-d₆) δ 12.13 (br. s, 1H), 8.64 (d, J=5.1Hz, 4H), 7.67 (d, J=4.8 Hz, 2H), 7.52 (d, J=4.8 Hz, 2H), 5.03 (t, J=4.4Hz, 1H), 4.54 (d, J=4.4 Hz, 2H), 2.34 (s, 3H); IR (KBr) ν 3400, 1670,1600, 1460, 1430, 1260, 1000, 840 cm⁻¹; Anal. Calcd. for C₁₇H₁₅N₃O₂0.75H₂O: C, 66.55; H, 5.42; N, 13.69. Found: C, 66.80; H, 5.08; N,13.37.

Example 34 3-(1-Rydroxyethyl)-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole(1.11 g; 4.0 mmol) in EtOH (12 mL) was added sodium borohydride (NaBH4)(0.15 g; 4.0 mmol) at room temperature. After stirring for 1 hour,additional NaBH4 (0.05 g; 1.3 mmol) was added. The mixture was stirredfor 30 minutes, and then volatiles were removed by evaporation. Water(30 mL) was added to the reaction mixture, and the whole was extractedwith ethyl acetate-EtOH (10:1, 70 mL×3). Combined organic layers werewashed with water (50 mL), brine (50 mL), dried over MgSO₄, andconcentrated in vaciio. The residue was recrystallized from EtOH to givethe title compound (0.432 g, 39% yield) as a colorless solid.

mp: 250-252° C.; ¹H-NMR (DMSO-d₆) δ 11.29 (s, 1H), 8.59 (dd, J=6.2, 1.8Hz, 2H), 8.56 (dd, J=6.2, 1.8 Hz, 2H), 7.56 (dd, J=4.8, 1.8 Hz, 2H),7.54 (dd, J=4.8, 1.8 Hz, 2H), 5.00 (s, 1H), 4.98 (q, J=6.6 Hz, 1H), 2.38(s, 3H), 1.45 (d, J=6.6 Hz, 3H); Anal. Calcd. for C₁₇H₁₇N₃O 0.1H₂O: C,72.63; H, 6.17; N, 14.95. Found: C, 72.47; H, 6.14; N, 14.86.

Example 354-Methyl-3-(methyloxyimino-1-ethyl-2,5-di(4-pyridyl-1H-pyrrolehydrochloride

To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole(0.7 g; 2.5 mmol) in ethanol-pyridine (8 mL×2 mL) was addedO-methylhydroxylamine hydrochloride (0.27 g; 3.3 mmol) at roomtemperature, and the mixture was stirred for 15 hours. The resultingprecipitates were collected by filtration, and the obtained solid wasrecrystallized from EtOH-MeOH to give the title product (0.16 g, 19%yield) as a colorless solid.

mp: 213-216° C. (recryst. from EtOH); ¹H-NMR (DMSO-d₆) δ 13.1 (s, 1H),8.90 (d, J=6.5 Hz, 2H), 8.87 (d, J=7.0 Hz, 2H), 8.37 (d, J=7.0 Hz, 2H),7.81 (d, J=6.5 Hz, 2H), 3.90 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); MS(EI) m/z 306 (M⁺); Anal. Calcd. for C₁₈H₁₈N₄O 1.8HCl 1.6H₂O: C,53.94; H,5.78; N, 13.98; Cl, 15.92. Found: C, 53.65; H, 5.57; N, 13.76; Cl,15.67.

Example 36 3-Acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole-N,N′-dioxidesand a Mixture of4-{3-acetyl-4-methyl-5-(4-pyridyl)-1H-pyrrol-2-yl}pyridine-N-oxide and4-{3-acetyl-4-methyl-2-(4-pyridyl)-1H-pyrrol-5-yl}pyridine-N-oxide(2.5:1)

To a stirred suspension of3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (1.0 g; 3.6 mmol) inCH₂Cl₂ (15 mL) was added m-chloroperbenzoic acid (MCPBA) (0.71 g; 2.9mmol) at room temperature. After stirring for 30 minutes, volatiles wereremoved by evaporation. The residue was purified by flash chromatographyeluting with CH₂Cl₂—EtOH (10:1→6:1) to give mono-oxide (0.24 g, 23%yield) as less polar product and dioxide (0.2 g, 18% yield) as polarproduct.

less polar product:

mp: >280° C.; ¹H-NMR (DMSO-d₆) δ 11.98 (s, 1H), 8.65 (d, J=7.3 Hz, 2H),8.27 (d, J=7.3 Hz, 2H), 7.57 (d, J=7.3 Hz, 2H), 7.52 (d, J=7.3 Hz, 2H),2.31 (s, 3H), 2.17 (s, 3H); MS (EI) m/z 293 (M⁺); Anal. Calcd. forC₁₇H₁₅N₃O₂ 0.1H₂O: C, 69.19; H, 5.19; N, 14.24. Found: C, 69.14; H,5.10; N, 14.18.

more polar product:

mp: 301-302° C. (recryst. from ethyl acetate); ¹H-NMR (DMSO-d₆) δ 11.91(s, 1H), 8.28 (d, J=6.3 Hz, 2H), 8.27 (d, J=6.3 Hz, 2H), 7.56 (d, J=6.3Hz, 2H), 7.54 (dd, J=6.3 Hz, 2H), 2.31 (s, 3H), 2.24 (s, 3H); MS (EI)m/z 309 (M⁺); Anal. Calcd. for C₁₇H₁₅N₃O₃: C, 66.01; H, 4.89; N, 13.58.Found: C, 65.65; H, 4.88; N, 13.41.

Exanmple 373-Acetyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole(1.0 g, 3.6 mmol) in DMF (5 mL) was added NaH (60% oil dispersion; 0.29g, 7.2 mmol) at room temperature. The mixture was heated at 70-80° C.for 30 minutes, and after cooling to 0° C., chloromethyl methyl ether(0.41 mL, 5.4 mmol) was added. The mixture was stirred for 15 hours, andsaturated aqueous NaHCO₃ (30 mL) was added to the reaction mixture. Thewhole was extracted with ethyl acetate (50 mL×3). Combined organiclayers were washed with water (50 mL), brine (50 mL), dried over MgSO₄,and concentrated in vactio. The residual oil was purified by preparativeTLC (1 mm×3) to give the title compound (0.1 g, 9% yield) as a lightbrown powder.

¹H-NMR (CDCl₃) δ 8.78-8.71 (m, 4H), 7.47-7.40 (m, 4H), 4.68 (s, 2H),3.12 (s, 3H), 2.26 (s, 3H), 2.03 (s, 3H); MS (EI) m/z 321 (M⁺); Anal.Calcd. for C₁₉H₁₉N₃O₂ 0.6H₂O: C, 68.70; H, 6.13; N, 12.65. Found: C,68.61; H, 5.92; N, 12.31.

Example 383-Acetyl-1-(2-methoxy-1-ethyl)-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

The title compound was prepared according to the procedure of Example 37using 2-chloro ethyl methyl ether instead of chloromethyl methyl ether.

mp: oil; ¹H-NMR (CDCl₃) δ 8.76 (dd, J=4.4, 1.4 Hz, 2H), 8.72 (dd, J=4.4,1.4 Hz, 2H), 7.38 (dd, J=4.4, 1.4 Hz, 2H), 7.29 (dd, J=4.4, 1.4 Hz, 2H),3.89 (t, J=5.9 Hz, 2H), 3.00 (t, J=5.9 Hz, 2H), 2.97 (s, 3H), 2.21 (s,3H), 1.98 (s, 3H).

Example 39 3-Hydroxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

3-Ethoxycarbonyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

The subtitle compound was prepared according to the procedure of Example37 using 3-ethoxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole insteadof 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole.

¹H-NMR (CDCl₃) δ 8.72 (t, J=1.8 Hz, 2H), 8.70 (t, J=1.8 Hz, 2H),7.42-7.38 (m, 4H), 4.72 (s, 2H), 4.14 (q, J=7.0 Hz, 2H), 3.08 (s, 3H),2.29 (s, 3H), 1.06 (t, J=7.0 Hz, 3H).

3-Hydroxymethyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

To a stirred suspension of lithium aluminum hydride (LAH) (88 mg, 2.31mmol) was added3-ethoxycarbonyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole(270 mg, 0.77 mmol) at 0° C. under nitrogen. After stirring for 2 hours,the reaction mixture was allowed to warm to room temperature and stirredfor 3 days. Saturated aqueous ammonium chloride solution (50 mL) wasadded to the mixture, and the whole was extracted with ethyl acetate (70mL×2). Combined organic layers were washed. with brine (50 mL), driedover MgSO₄, and concentrated il vacuo to afford the subtitle compound(180 mg, 5.8% yield) as a solid.

mp: 181-183° C.; ¹H-NMR (CDCl₃) δ 8.70-8.66 (m, 4H), 7.57 (dd, J=4.4 Hz,1.5 Hz, 2H), 7.44 (dd, J=4.4 Hz, 1.5 Hz, 2H), 4.82 (s, 2H), 4.53 (s,2H), 3.19 (s, 3H), 2.22 (s, 3H).

3-Hydroxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

3-Hydroxymethyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole(150 mg, 0.49 mmol) was dissolved in 10% aqueous HCl solution (20 mL)and the mixture was stirred for 1 day at room temperature then heated atreflux temperature for 1 hour. After cooling, the mixture wasneutralized with saturated aqueous sodium bicarbonate solution.Volatiles were removed by evaporation, and the residue was suspended inEtOH. After removal of insolubles by filtration, the filtrate wasconcentrated in vacto. The crude product was purified by flashchromatography eluting with CH₂Cl₂—EtOH (5:1), followed byrecrystallization from EtOH to give the title compound (30 mg, 23%yield) as a solid.

mp: 258-261° C.; ¹H-NMR (DMSO-d₆) δ 11.44 (br. s, 1H), 8.61-8.56 (m,4H), 7.72-7.56 (m, 4H), 4.94 (t, J=4.8 Hz, 1H), 4.41 (d, J=4.8 Hz, 2H),2.29 (s, 3H); Anal. Calcd. for C₁₆H₁₅N₃O 0.8H₂O: C, 68.70; H, 5.98; N,15.02. Found: C, 68.90; H, 5.56; N, 14.71.

Example 40 3-Aminocarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole

3-Cyano-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (200 mg, 0.77 mmol) wasdissolved in sulfuric acid (3 mL) and the mixture was stirred for 15hours at 85° C. After cooling, fuing sulfuric acid (1 drop) was added tothe reaction mixture and stirred for 1 hour at room temperature. Thereaction mixture was neutralized by saturated aqueous NaHCO₃ solution,and the resulting precipitates were collected by filtration.Recrystallization from EtOH gave the title compound (110 mg, 51% yield).

mp: 212-215° C.; IR (KBr) ν 3400, 1640, 1600, 1480, 1420, 1380, 1320,1000, 820, 520 cm⁻¹; ¹H-NMR (DMSOd₆) δ 11.63 (br. s, 1H), 8.60 (d, J=6.2Hz, 2H), 8.55 (d, J=6.2 Hz, 2H), 7.63 (d, J=6.2 Hz, 2H), 7.62 (br. s,1H), 7.57 (d, J=6.2 Hz, 2H), 7.34 (br, s, 1H), 2.26 (s, 3H); MS (EI) m/z278 (M⁺);

Example 41 3-Carboxyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole MorpholiniumSalt

To a solution of3-allyloxycarbonyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (100 mg, 0.313mmol) in TBIF (4 mL) including 10% DMSO were added Pd(PPh₃)₄ (36.2 mg,0.0313 mmol) and morpholine (0.27 ml, 3.13 mmol) at room temperature.The mixture was stirred for 5 hours at the same temperature under Ar inthe dark and then evaporated to give an oily residue, which wascrystallized from ethyl acetate. The solid was recrystallized from MeOHto afford 30.2 mg of the title compound as a morpholinium salt.

mp: 223-224° C. (Recryst. from MeOH); IR (KBr) ν 3400, 1600, 1560, 1480,1430, 1370, 1310, 1220, 830 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.84 (br. s, 1H),8.61-8.57 (m, 4H), 7.63-7.54 (m, 4H), 3.50 (t, J=4.6 Hz, 2H), 2.67 (t,J=4.8 Hz, 2H), 2.54 (s, 5H), 2.38 (s, 2H); MS (FAB) m/z, 280 (M⁺H)⁺.

Example 42 3-Acetyl-2-methyl-4,5-di(4-pyridyl)1H-pyrrole

To a stirred solution of y-pyridoin (1.8 g, 8.4 mmol) (preparedaccording to the procedure of litrature; Japanese Kokai PublicationH07-00273 7) and 2,4-pentanedione (1.35 g, 13.5 mmol) in acetic acid (20mL) was added ammonium acetate (2.6 g, 33.7 mmol) at room temperature.The resulting mixture was heated at reflux temperature for 9 hours, andstirred at room temperature overnight. Volatiles were removed byevaporation, and the mixture was neutralized by saturated aqueousNaHCO₃. The whole was extracted with ethyl acetate (50 mL×3),CH₂Cl₂—EtOH (5:1, 50 mL×2), dried over MgSO₄, and concentrated invacito. The residue was purified by flash chromatography eluting withCH₂Cl₂—EtOH (15:1->10:1) to give the title compound (0.2 g, 9% yield) asa colorless solid.

mp: 236-239° C.; ¹H-NMR (DMSO-d₆) δ 12.03 (s, 1H), 8.57 (d, J=5.9 Hz,2H), 8.38 (d, J=6.2 Hz, 2H), 7.27 (d, J=5.9 Hz, 2H), 7.03 (d, J=6.2 Hz,2H), 2.53 (s, 3H), 1.93 (s, 3H); Anal. Calcd. for C₁₇H₁₅N₃O 0.2H₂O: C,72.68; H, 5.53; N, 14.96. Found: C, 72.72; H, 5.43; N, 14.89.

Example 43 3-Acetyl-2-methyl-5-(4-pyridyl)-1H-pyrrole

A mixture of 4-(bromoacetyl)pyridine hydrobromide (2.64 g, 10 mmol),2,4-pentadione (1.62 g, 16 mmol), and NH₄OAc (3.1 g, 40 mmol) in AcOH(25 mL) was heated under reflux temperature for 17 hours. After cooling,10% aqueous KOH solution and saturated aqueous NaHCO₃ solution was addedto this resulting solution until becoming basic solution (pH=8˜9). Thewhole was extracted with ethyl acetate (50 mL×3), and the combinedorganic layers were washed with brine (20 mL), dried over MgSO₄, andconcentrated in vactio. The residue was purified by flash chromatographyeluting with CH₂Cl₂—EtOH (20-15:1) to afford the title compound (70 mg,4% yield).

mp 236-237° C.; ¹H-NMR (DMSO-d₆) δ 11.90 (s, 1H), 8.50 (d, J=6.2 Hz,2H), 7.62 (d, J=6.2 Hz, 2H), 7.28 (d, J=2.6 Hz, 1H), 2.50 (s, 3H), 2.36(s, 3H); IR (nujol) ν 1650, 990, 730 cm⁻¹; MS (EI) m/z 200 (M⁺); Anal.Calcd for C₁₂H₁₂N₂O: C, 71.68; H, 6.06; N, 13.86. Found: C, 71.98, H,6.04; N, 13.99.

Example 44 3-Ethoxycarbony-4-methyl-5phenyl-2-(4-pyridyl)-1H-pyrrole

A mixture of 1-amino-1-phenyl-propan-2-on hydrochloride (10.5 g, 50.5mmol), ethyl isonicotinoylacetate (8.1 g, 42.1 mmol), and ammoniumacetate (6.5 g, 84.2 mmol) in acetic acid (50 mL) was heated underreflux temperature for 6 hours. After cooling, the mixture was dilutedwith ice-water (50 mL). The whole was extracted with CH₂Cl₂ (30 mL×3),and the combined organic layers were dried over MgSO₄, and concentratedin vaciio. The residue was purified by flash chromatography eluting withhexane-ethyl acetate (2 : 1) to afford the title product (2.1 g, 16%yield) as a pale yellow solid.

mp 179-181° C.; ¹H-NMR (CDCl₃) δ 9.53 (s, 1H), 8.49 (d, J=5.9 Hz, 2H),7.50-7.27 (m, 7H), 4.24 (q, J=7.3 Hz, 2 H), 2.41 (s, 3H), 1.23 (t, J=7.3Hz, 3H); IR (KBr) ν 3000, 1698, 1600, 1470, 1250, 1070, 700 cm⁻¹; MS(EI) m/z 306 (M⁺); Anal. Calcd for C₁₉H₁₈N₂O 0.2 H₂O: C, 73.62; H, 5.98;N, 9.04. Found: C, 73.67; H, 5.85; N, 9.00.

Example 45 3-Actyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole Method A

3-Acetyl-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole(Step 1)

To a stirred solution of 3-acetyl-2,4-dimethyl-1H-pyrrole (commerciallyavailable from Aldrich Chem. Co. Inc., 1.50 g, 10.6 mmol) in DMF (40 mL)was added NaH (60% oil dispersion, 0.85 g, 21.2 mmol) at roomtemperature under nitrogen. After stirring for 30 minutes at roomtemprature the resulting suspension was cooled to 0° C. and added2-(trimethylsilyl)ethoxymethyl chloride (3 mL, 15.9 mmol). The reactionmixture was warm to room temperature and stirred for 3 hours. Themixture was quenched with aqueous saturated NaHCO₃ solution, and thewhole extracted with diethyl ether (100 mL×2). The combined organiclayers were washed with brine (50 mL), dried over MgSO₄, concentratediii vaciio. Chromatographic purification of the crude product elutingethyl acetate-hexane (1:10) gave the subtitle product (2.32 g, 82%yield).

¹H-NMR (CDCl₃) δ 6.37 (s, 1H), 5.09 (s, 2H), 3.44 (t, J=8.1 Hz, 2H),2.50 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H), 0.87 (t, J=8.1 Hz, 2H), −0.04(s, 9H).

3-Acetyl-5-bromo-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl-}-1H-pyrrole(Step2)

To a stirred solution of3-acetyl-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole(1.75 g, 6.91 mmol) in THF (40 mL) was added N-bromosuccinimide (NBS;1.29 g, 7.25 mmol) at −78° C. under nitrogen. After stirring for 30minutes at same temperature, the mixture was allowed to warm to roomtemperature and stirred for 1 hour. Volatiles were removed byevaporation and the residue was purified by flash chromatography elutingwith ethyl acetate-hexane (1:15) to give the subtitle product (1.50 g,67%).

¹H-NMR (CDCl₃) δ 5.30 (s, 2H), 3.56 (t, J=8.1 Hz, 2H), 2.57 (s, 3H),2.44 (s, 3H), 2.26 (s, 3H), 0.91 (t, J=8.1 Hz, 2H), 0.00 (s, 9H).

3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole(Step 3)

To a stirred solution of3-acetyl-5-bromo-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole(309 mg, 0.85 mmol) in toluene (5 mL) was added diethyl(4-pyridyl)borane[prepared according to the method of M. Terashima et al., Heterocycles,1984, 22, 2471] (250 mg, 1.70 mmol), potassium hydroxide (85% purity,168 mg, 2.55 mmol), and tetrakis(triphenylphosphine)palladium (0) (100mg, 0.085 mmol) at room temperature under nitrogen. The mixture washeated at reflux temperature for 3 hours. After cooling, volatiles wereremoved by evaporation. The residue was purified by flash chromatographyeluting with ethyl acetate-hexane (1:1) to give the title product (105mg, 36% yield).

¹H-NMR (CDCl₃) δ 8.73-8.66 (m, 2H), 7.31-7.26 (m, 2H), 5.05 (s, 2H),3.38 (dd, J=8.3 Hz, 8.1 Hz, 2H), 2.62 (s, 3H), 2.50 (s, 3H), 2.22 (dd,J=8.3 Hz, 8.1 Hz, 2H), −0.01 (s, 9H).

3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole (Step 4)

3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole(1.12 g, 3.39 mmol) was dissolved with EtOH (10 mL) and 10% aqueous HClsolution (30 mL) and the mixture was heated at 85° C. for 4 hours. Aftercooling, the mixture was neutralized with saturated aqueous NaHCO₃solution. The whole was extracted with ethyl acetate (150 mL×2), and thecombined organic layers were washed with brine (50 mL), dried overMgSO₄, and concentrated in vactio. The resulting solid was a mixture of3-acetyl-1-hyroxymethyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole and3-acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole. This mixture wassuspended with saturated aqueous sodium acetate solution and then heatedat reflux temperature for 15 minutes. After cooling, this mixture wasextracted with ethyl acetate (100 mL×2). The combined organic layerswere washed with brine (50 mL), dried over MgSO₄, and concentrated invacuo. The residue was recrystallized from ethyl acetate-hexane to givethe title product (205 mg, 28% yield) as a pale yellow solid.

mp: 205-207° C.; IR: ν 3250, 1620, 1605, 1460, 1420, 1170, 1080, 955,820 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.52 (br. s, 1H), 8.56 (dd, J=4.4 Hz, 1.5Hz, 2H), 7.42 (dd, J=4.4 Hz, 1.5 Hz, 2H), 2.50 (s, 3H), 2.37 (s, 6H); MS(EI) m/z 214 (M⁺); Anal. Calcd. for C₁₃H₁₄N₂O 0.1H₂O: C, 72.27; H, 6.62;N, 12.96. Found: C, 72.09; H, 6.75; N, 12.60.

Method B

3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrolecan be prepared by the use of tri-n-butyl(4-pyridyl)stannane instead ofdiethyl(4-pyridyl)borane in step 3 as follows;

To a stirred solution of3-acetyl-5-bromo-2,4-dimethyl-1-{2-(trimethylsilyl)ethoxymethyl}-1H-pyrrole(1.50 g, 4.65 mmol) in dioxane (50 mL) was addedtri-butyl(4-pyridyl)stannane [prepared according to the method of V.Snieckus et al., J. Org. Chem., 1995, 60, 292] (1.71 g, 4.65 mmol),lithium chloride (0.49 g, 11.6 mmol) andtetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 2 days, additional tributyl(4-pyridyl)stannane (1.00 g, 2.72 mmol)and tetrakis(triphenylphosphine)palladium (0.50 g, 0.43 mmol) were addedto the reaction mixture. After stirring at reflux temperature for 3days, tributyl(4-pyridyl)stannane (1.00 g, 2.72 mmol) andtetrakis(triphenylphosphine)palladium (0.37 g, 0.32 mmol) were addedagain to the mixture. Then the mixture was stirred at reflux temperaturefor additional 2 days. After cooling, the mixture was filtered throughcelite pad, and the filtrate was concentrated in vactio. The residue waspurified by flash chromatography eluting with ethyl acetate-hexane(1:2.5) to give the subtitle product (1.12 g, 73% yield).

Method C

Alternatively, 3-acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole wasprepared more efficiently as follows;

3-Acetyl-5-bromo-2,4-dimethyl-1H-pyrrole (Step 1)

To a stirred suspension of 3-acetyl-2,4-dimethyl-1H-pyrrole (2.89 g,21.1 mmol) in THF (80 mL) was added NBS (3.75 g, 21.1 mmol) at −78° C.under nitrogen. After stirring for 30 minutes at same temperature, themixture was allowed to warm to room temperature and stirred for 1 hour.Sodium sulfite (4.3 g) was added to the mixture and volatiles wereremoved by evaporation. Water (100 mL) was added to the mixture, and theprecipitates were collected by filtration to give 5.33 g (quant.including water) of the subtitle product.

¹H-NMR (CDCl₃) δ 8.08 (br. s, 1H), 2.49 (s, 3H), 2.42 (s, 3H), 2.22 (s,3H).

3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole (Step 2)

To a stirred solution of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole (5.33g, 21.1 mmol, including water) in dimethoxyethane (DME; 60 mL) addedwater (20 mL), sodium bicarbonate (5.32 g, 63.3 mmol), 4-pyridineboronicacid [prepared according to the method of Fischer F. C. et al., J. Red.Trav. Chim. Pays-Bays, 1965, 84, 439. ] (3.11 g, 25.3 mmol) andbis(triphenylphosphine)palladium(II)chloride (1.48 g, 2.11 mmol) at roomtemperature under nitrogen. The mixture was heated at reflux temperaturefor 8 hours, 4-pyridineboronic acid (0.5 g, 4.07 mmol) andbis(triphenylphosphine)palladium(II)chloride (1.48 g, 2.11 mmol) wereadditionally added to the reaction mixture and stirred at refluxtemperature for 6 hours. After cooling, the reaction mixture wasfiltered through celite pad. The filtrate was diluted with ethyl acetate(150 mL), and the whole was washed with water (50 mL). The aqueous layerwas extracted with ethyl acetate (150 mL), and the combined organiclayers were washed with brine (50 mL) and 10% aqueous HCl solution (100mL×2). The combined acidic aqueous layers were neutralized withsaturated aqueous NaHCO₃ solution. The whole was extracted with ethylacetate (100 mL×3), and the combined organic layers were dried overMgSO₄, and concentrated in vacuo. The resulting solids were washed withdiethylether to give 2.00 g of crude product, which was recrystallizedfrom MeOH to give the title product (1. 13 g, 25% yield).

Example 46 3-Acetyl-4-methyl-2-phenyl-5-(4-pyridyl)-1H-pyrrole

3-Acetyl-4-methyl-2-phenyl-1H-pyrrole and3-Acetyl-4-methyl-5-phenyl-1H-pyrrole (Step 1)

NaH (60% oil dispersion; 700 mg, 17.5 mmol) was washed with dry Et₂O (10mL×2) and dried under reduced pressure. To NaH was added a solution ofN-(benzotriazol-1-yl-methyl)-α-(methylthio)phenylimine (Katritzky, A. R.et. al., Tetrahedron, 1995, 51, 13271) (1.41 g, 5.0 mmol) and3-penten-1-on (0.84 mL, 8.6 mmol) in THF (20 mL) and DMSO (5 mL). Theresulting mixture was stirred at 40° C. for 2 hours, and was quenched byH₂O (30 mL). The whole was extracted with Et₂O (30 mL×2), and thecombined organic layers were washed with brine (20 mL), dried over MgSO₄and concentrated in vaciio. The residue was purified by flashchromatography eluting with hexane-ethyl acetate (5:1) to give the lesspolar product (0.58 g, 58% yield) as a solid and the polar product (0.22g, 22% yield) as a white solid.

3-Acetyl-4-methyl-2-phenyl-1H-pyrrole (less polar):

mp 156-157° C.; ¹H-NMR (CDCl₃) δ 8.14 (br. s, 1H), 7.41 (s, 5H),6.59-6.56 (m, 1H), 2.30 (d, J=1.1 Hz, 3H), 2.09 (s, 3H); MS (EI) m/z 199(M⁺); Anal. Calcd for C₁₃H₁₃NO: C, 78.36; H, 6.58; N, 7.03. Found: C,78.47; H, 6.57; N, 7.12.

3-Acetyl-4-methyl-5-phenyl-1H-pyrrole (polar):

mp 156-157° C.; 1H-NMR (CDCl₃) δ 8.43 (br. s, 1H), 7.47-7.37 (m, 5H),7.36-7.27 (m, 1H), 2.45 (s, 3H), 2.44 (s, 3H); MS (EI) m/z 199 (M⁺);Anal. Calcd for C₁₃H₁₃NO: C, 78.36; H, 6.58; N, 7.03. Found: C, 78.36;H, 6.56; N, 6.96.

3-Acetyl-5-bromo-4-methyl-2-phenyl-1H-pyrrole (Step 2)

The subtitle compound was prepared according to the procedure of Example45 (Method C) using 3-acetyl-4-methyl-2-phenyl-1H-pyrrole instead of3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

mp 158-159° C.;

¹H-NMR (CDCl₃) δ 8.15 (s, 1H), 7.50-7.35 (m, 5H), 2.24 (s, 3H), 2.06 (s,3H)MS; (EI) m/z 279 (M⁺), 277 (M⁺).

3-Acetyl-4-methyl-2-phenyl-5-(4-pyridyl)-1H-pyrrole (Step 3)

To a stirred suspension of 4-acetyl-2-bromo-3-methyl-5-phenyl-1H-pyrrole(139 mg, 0.50 mmol), 4-pyridylboronic acid (307 mg, 2.5 mmol) in DME(1.5 mL) and saturated aqueous NaHCO₃ (0.50 mL) was added Pd(PPh₃)₂Cl₂(70 mg, 0.10 mmol) under nitrogen. The mixture was heated under refluxfor 12 hours. After cooling, the mixture was diluted with ethyl acetate(5 mL) and water (10 mL). The organic layer was separated, and then theaqueous layer was extracted with ethyl acetate (5 mL×2). The combinedorganic layers were extracted with 1M aqueous HCl (3 mL×2). The combinedaqueous layes were neutralized by the addition of 10% aqueous KOH untilbeing pH=8. The whole was extracted with CH₂Cl₂ (10 mL×3), the combinedorganic layers were dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography eluting with hexane-ethylacetate (1:2→EtOAc only) to provide the title product (42 mg, 30% yield)as a colorless solid.

mp 202-203° C.; IR (nujol) 1670, 1650, 1600, 720 cm⁻¹; ¹H-NMR (CDCl₃) δ8.59 (dd, J=4.6, 1.7 Hz, 3H), 7.47 (s, 5H), 7.35 (dd, J=4.6, 1.7 Hz,2H), 2.47 (s, 3H), 2.11 (s, 3H); MS (EI) m/z 276 (M⁺); Anal. Calcd forC₁₈H₁₆N₂O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.21; H, 5.75; N,9.96.

Example 47 3-Acetyl-4-methyl-5-phenyl-2-(4-pyridyl)-1H-pyrrole

The title compound was prepared according to the procedure of Example 46using 3-acetyl-4-methyl-5-phenyl-1H-pyrrole instead of3-acetyl-4-methyl-2-phenyl-1H-pyrrole in step 2.

mp 208-209° C.; IR (KBr) 3100, 1730, 1700, 1680, 1450, 1420, 1350, 990,970, 825, 760, 700 cm⁻¹; ¹H-NMR (CDCl₃) δ 8.62 (br. s, 3H), 7.55-7.30(m, 7H), 2.37 (s, 3H), 2.31 (s, 3H).; MS (EI) m/z 276 (M⁺); Anal. Calcdfor C₁₈H₁₆N₂O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.06; H, 5.80; N,10.01.

Example 48 3-Acetyl-4-methyl-5-(4-pyridyl)-1H-pyrrole

3-Acetyl-4-methyl-5-bromo-1H-pyrrole (Step 1)

The subtitle compound was prepared according to the procedure of Example45 (Method C) using 3-acetyl-4-methyl-1H-pyrrole instead of3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

¹H-NMR (CDCl₃) δ 8.46 (br. s, 1H), 7.35 (d, J=3.3 Hz, 1H), 2.39 (s, 3H),2.26 (s, 3H).

3-Acetyl-4-methyl-5-(4-pyridyl)-1H-pyrrole (Step 2)

The title compound was prepared according to the procedure of Example 45(Method C) using 3-acetyl-4-methyl-5-bromo-1H-pyrrole instead of3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.

mp: 210-211° C.; IR (KBr) ν 1650, 1600, 1490, 1400, 1360, 1200, 1000,820, 720 cm⁻¹; ¹H-NMR (DMSO-d₆) δ 11.86 (br. s, 1H), 8.57 (d, J=5.9 Hz,2H), 7.81 (s, 1H), 7.46 (d, J=5.9 Hz, 2H), 2.43 (s, 3H), 2.36 (s, 3H);Anal. Calcd. for C₁₂H₁₂N₂O 0.1H₂O: C, 71.34; H, 6.09; N, 13.87. Found:C, 71.16; H, 6.07 ; N, 13.54.

Example 49 3-Methyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole

3-Methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (Step 1)

The subtitle compound was prepared according to the literature procedure(Hauptmann, S. et al., Z. Chem., 1966, 3, 107. Ravina, E. et al., Bio.Med. Chem. Lett., 1995, 5, 579.). A mixture of anti-pyruvic aldehyde1-oxime (1.3 g, 15 mmol), 1,3-cyclohexanedione (1.7 g, 15 mmol), glacialacetic acid (12 mL) and water (3.0 mL) was stirred vigorously at roomtemperature. Zinc dust (3 g) was added slowly keeping the temperaturebelow 60° C. After addition, this resulting brown solution was heatedunder reflux temperature for 2 hours. After cooling, the reactionmixture was basified by an addition of 1 M aqueous KOH. The whole wasextracted with CH₂Cl₂ (50 mL×3), and the combined organic layers weredried over MgSO₄, and concentrated in vaciio. The residue was purifiedby flash chromatography eluting with hexane-ethyl acetate (3:1→EtOAconly) to afford the subtitle compound (1.0 g, 46% yield) of as a yellowsolid.

¹H-NMR (CDCl₃) δ 8.40 (br. s, 1H), 6.40 (s, 1H), 2.78 (t, J=6.3 Hz, 2H),2.45 (t, J=6.5 Hz, 2H), 2.29 (d, J=1.1 Hz, 3H), 2.17-2.07 (m, 2H).

2-Bromo-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole (Step 2)

The subtitle compound was prepared according to the procedure of Example45 (Method C) using 3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indole insteadof 3-acetyl-2,4-dimethyl-1H-pyrrole in step 1. ¹H-NMR (CDCl₃) δ 8.19(br. s, 1H), 2.75 (t, J=6.2 Hz, 2H), 2.45 (t, J=6.4 Hz, 2H), 2.23 (s,3H), 2.17-2.07 (m, 2H); MS (EI) m/z 229 (M), 227 (M⁺);

3-Methyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole (Step 3)

The title compound was prepared according to the procedure of Example 45(Method C) using 2-bromo-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indoleinstead of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.

mp 248-249° C.; ¹H-NMR (CDCl₃) δ 9.58 (br. s, 1H), 8.56 (dd, J=4.6, 1.6Hz, 2H), 7.35 (dd, J=4.6, 1.6 Hz, 2H), 2.88 (t,J=6.2 Hz, 2H), 2.55 (s,3H), 2.50 (t,J=6.4 Hz, 2H), 2.21-2.11 (m, 2H); MS (EI) m/z 227, 226(M⁺); Anal. Calcd. for C₁₄H₁₄N₂O 0.7H₂O: C, 70.39; H, 6.20; N, 11.73.Found: C, 70.45; H, 6.12;N, 11.64.

Example 50 3-Acetyl-2-bromo-4-methyl-5-(4-pyridyl)-1IH-pyrrole

The title compound was prepared according to the procedure of Example 45(Method C) using 3-acetyl-4-methyl-5-(4-pyridyl)-1H-pyrrole instead of3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

mp 205-206° C.; ¹H-NMR (CDCl₃) δ 8.51(br. s, 3H), 7.34 (d, J=5.9 Hz,2H), 2.62 (s, 3H), 2.45 (s, 3H); MS (EI) m/z 280 (M⁺), 278 (M⁺).

Example 51 3-Acetyl-2-(4-fluorophenyl)4-methyl-5-(4-pyridyl)-1H-pyrrole

The title compound was prepared from3-acetyl-2-bromo-4-methyl-5-(4-pyridyl)-1H-pyrrole according to theprocedure of Example 46 using 4-fluorophenylboronic acid instead of4-pyridylboronic acid in step 3.

mp 202-203° C.; IR (KBr) ν 2860, 2760, 1650, 1600, 1495, 1460, 1430,1225, 1100, 840, 830 cm⁻¹; ¹H-NMR (CDCl₃) δ 8.60 (br. s, 1H), 8.59 (d,J=6.2 Hz, 2H), 7.45 (dd, J=8.4, 5.1 Hz, 2H), 7.34 (dd, J=5.1, 1.3 Hz,2H), 7.17 (t, J=8.4 Hz, 2H), 2.46 (s, 3H), 2.11 (s, 3H); MS (EI) m/z 294(M⁺); Anal. Calcd for C₁₈H₁₅N₂OF 0.3 H₂O: C, 72.13; H, 5.25; N, 9.35.Found: C, 72.05; H, 5.27; N, 9.05.

Example 52 3-Acetyl-4-methyl-5-(4-pyridyl)-2-(2-thienyl)-1H-pyrrole

The title compound was prepared from3-acetyl-2-bromo-4-methyl-5-(4-pyridyl)-1H-pyrrole according to theprocedure of Example 46 using 2-thienylboronic acid instead of4-pyridylboronic acid in step 3.

mp 231-232° C.; IR (KBr) 3200, 1650, 1600, 1430, 1350, 1220, 1000, 820,700 cm⁻¹; ¹H-NMR (CDCl₃) δ 8.65-8.57 (m, 2H), 8.50 (br. s, 1H), 7.46(dd, J=5.1, 1.1 Hz, 1H), 7.34 (dd, J=4.4, 1.8 Hz, 2H), 7.25 (d, J=1.1Hz, 1H), 7.14 (dd, J=5.1, 3.7 Hz, 1H), 2.45 (s, 3H), 2.25 (s, 3H); MS(EI) m/l 284, 283, 282 (M⁺); Anal. Calcd. for C₁₆H₁₄N₂OS: C, 68.06; H,5.00; N, 9.92. Found: C, 67.74; H, 5.00; N, 9.68.

Example 53 4-Oxo-3-phenyl-1-(4-pyridyl)-4,5,6,7-tetrahydroisoindole

7-Oxo-1-phenyl-4,5,6,7-tetrahydroisoindole and4-Oxo-1-phenyl-4,5,6,7-tetrahydroisoindole (Step 1)

NaH (60% oil dispersion; 420 mg, 10.5 mmol) was washed with Et₂O (2×15mL) and dried under reduced pressure. To NaH was added a solution ofN-(benzotriazole-1-ylmethyl)-α-(methylthio)phenylimine (988 mg, 3.5mmol) and 2-cyclohexen-1-one (0.41 mL, 4.3 mmol) in THF (12 mL) and DMSO(3 mL) at 0° C. under N₂. The reaction mixture was stirred at 40° C. for2 hours, and was quenched by water (15 mL). The whole was extracted withEt₂O (2×15 mL) and ethyl acetate (15 mL), and the combined organiclayers were washed with brine (15 mL), dried over MgSO₄ and filtered.The filtrate was concentrated and the residue (isomeric ratio=ca 6.6:1)was purified by flash chromatography eluting with hexane-ethyl acetate(5:1→2:1) to afford the less polar product (85 mg, 11% yield) and thepolar product (541 mg, 73% yield).

7-Oxo-1-phenyl-4,5,6,7-tetrahydroisoindole (less polar):

¹H-NMR (CDCl₃) δ 8.44 (br. s, 1H), 7.76 (dd, J=8.5, 1.9 Hz, 2H),7.45-7.29 (m, 3H), 6.61 (t, J=1.1 Hz, 1H), 2.76 (t, J=6.3 Hz, 2H), 2.53(t, J=6.5 Hz, 2H), 2.13-2.04 (m, 2H); MS (EI) m/z 221 (M⁺);

4-Oxo-1-phenyl-4,5,6,7-tetrahydroisoindole (polar):

¹H-NMR (CDCl₃) δ 9.18 (br. s, 1H), 7.50-7.37 (m, 5H), 7.33-7.23 (m, 1H),2.89 (t, J=5.9 Hz, 2H), 2.53 (dd, J=7.2, 5.7 Hz, 2H), 2.14-2.04 (m, 2H);MS (EI) m/z 221 (M⁺);

1-Bromo-4-oxo-3-phenyl-4,5,6,7-tetrahydroisoindole

The subtitle compound was prepared according to the procedure of Example45 (Method C) using 7-oxo-1-phenyl-4,5,6,7-tetrahydroisoindole insteadof 3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

¹H-NMR (CDCl₃) δ 8.38 (br. s, 1H), 7.72 (dd, J=7.7, 1.5 Hz, 2H),7.47-7.32 (m, 3H), 2.64 (t, J=6.2 Hz, 2H), 2.52 (t, J=6.5 Hz, 2H),2.13-2.03 (m, 2H); MS (EI) m/z 291 (M⁺), 289 (M⁺).

4-Oxo-3-phenyl-1-(4-pyriddy)-4,5,6,7-tetrahydroisoindole

The title compound was prepared according to the procedure of Example 45(Method C) using 1-bromo-4-oxo-3-phenyl-4,5,6,7-tetrahydroisoindoleinstead of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.

mp 259-260° C.; ¹H-NMR (CDCl₃) δ 8.75 (br. s, 1H), 8.63 (d, J=6.2 Hz,2H), 7.81-7.76 (m, 2H), 7.49-7.37 (m, 3H), 7.33 (dd, J=4.6, 1.6 Hz, 2H),3.00 (t, J=6.0 Hz, 2H), 2.59 (t, J=6.4 Hz, 2H), 2.20-2.10 (m, 2H); MS(EI) m/z 288 (M⁺);

Example 54 7-Oxo-3-phenyl-1-(4-pyridyl)-4,5,6,7-tetrahydroisoindole

1-Bromo-7-Oxo-3-phenyl-4,5,6,7-tetrahydroisoindole

The subtitle compound was prepared according to the procedure of Example45 (Method C) using 4-oxo-1-phenyl-4,5,6,7-tetrahydroisoindole insteadof 3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

¹H-NMR (CDCl₃) δ 8.95 (br. s, 1H), 7.47-7.26 (m, 5H), 2.88 (t, J=6.1 Hz,2H), 2.54 (t, J=6.4 Hz, 2H), 2.12-2.02 (m, 2H); MS (EI) m/z 291 (M), 289(M⁺);

7-Oxo-3-phenyl-1-(4-pyridyl)-4,5,6,7-tetrahydroisoindole

The title compound was prepared according to the procedure of Example 45(Method C) using 1-bromo-7-oxo-3-phenyl-4,5,6,7-tetrahydroisoindoleinstead of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.

mp 254-255° C.; IR (KBr) 2950, 1660, 1600, 1585, 1450, 1000, 820, 720,700 cm⁻¹; ¹H-NMR (CDCl₃) δ 8.91 (br. s, 1H), 8.68-8.60 (m, 2H), 7.76(dd, J=4.6, 1.6 Hz, 2H), 7.48 (d, J=4.4 Hz, 2H), 7.42-7.30 (m, 1H), 2.94(t, J=6.2 Hz, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.17-2.07 (m, 2H); MS (EI)m/z 288 (M⁺); Anal. Calcd for C₁₉H₁₆N₂O 0.1H₂O: C, 78.65; H, 5.63; N,9.65. Found: C, 78.40; H, 5.50; N, 9.55.

Example 554-Oxo-2-(4-pyridyl)-3,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indole

The title compound was prepared according to the procedure of Example 49using 2,2-dimethyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedionein step 1.

mp: 241-241.5° C.; IR (KBr) 2950, 1660, 1605, 1480, 1375, 1000, 825cm⁻¹;. ¹H-NMR (CDCl₃) δ 8.61 (dd, J=4.6, 1.7 Hz, 2H), 8.44 (br. s, 1H),7.31 (dd, J=4.6 Hz, 1.7 Hz, 2H), 2.71 (s, 2H), 2.55 (s, 3H), 2.37 (s,2H), 1.15 (s, 6H); MS (EI) 254(M⁺); Anal. Calcd for C₁₆H₁₈N₂O: C, 75.56;H, 7.13; N, 11.01. Found: C, 75.19, H, 7.21; N, 10.86.

Example 563-Methyl-4-oxo-6-phenyl-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole

The title compound was prepared according to the procedure of Example 49using 2-phenyl-1,3-cyclohexanedione instead of 1,3-cyclohexanedione instep 1.

mp: 256-257° C.; IR (KBr) 3220, 1620, 1600, 1485, 1440, 1410, 1380,1070, 820, 760, 700 cm⁻¹. ¹H-NMR (CDCl₃) δ 8.61 (d, J=6.2 Hz, 2H),7.35-7.25 (m, 7H), 3.62-3.49 (m, 1H), 3.15-3.06 (m, 2H), 2.80-2.76 (m,2H), 2.60 (s, 3H); MS (EI) 302 (M⁺); Anal. Calcd for C₂₀H₁₈N₂O 0.2H₂O:C, 78.97; H, 6.03; N, 9.21. Found: C, 79.00, H, 5.99; N, 9.12.

Example 57 3-Cyano-4-methyl-2,5-di(4-pyridyl-1H-pyrrole

The titled compound was prepared according to the procedure of Example 1using β-aminocrotononitrile instead of 2,4-pentanedione.

mp: 270-275° C. (Recryst. from ethyl acetate-EtOH); IR (KBr) ν 2200,1610, 1590, 14430, 1320, 1220, 1000, 820, 770, 680, 520 cm⁻¹; ¹H-NMR(DMSO-d₆) δ 12.52 (br. s, 1H), 8.73 (dd, J=4.8 Hz, 1.8 Hz, 2H), 8.68(dd, J=4.4 Hz, 1.5 Hz, 2H), 7.85(dd,J=4.8 Hz, 1.5 Hz, 2H), 7.64 (dd,J=4.4 Hz, 1.5 Hz, 2H), 2.37 (s, 3H); Anal. Calcd. for C₁₆H₁₂N₄ 1.0H₂O:C, 69.05; H, 5.07; N, 20.13. Found: C, 68.71; H, 4.98; N, 20.07.

The compounds of example 58-74 were prepared according to the procedureof example 46 using the corresponding boronic acids or tin reagentsinstead of 4-pyridineboronic acid in step 3.

Example 58 3-Acetyl-2-(3-aminophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 193-195° C.; ¹H-NMR (CDCl₃) δ 8.61(dd, J=4.8 Hz, 1.9 Hz, 2H), 8.42(bs, 1H), 7.34 (dd, J=4.8 Hz, 1.9 Hz, 2H), 7.28-7.21 (m, 1H), 6.84 (d,J=7.7 Hz, 1H), 6.77-6.74 (m, 2H), 3.81 (br. s, 2H), 2.45 (s, 3H), 2.17(s, 3H); MS (FAB) m/z 292 (M+H)⁺; Anal. Calcd. for C₁₈H₁₇N₃O 0.4H₂O: C,72.41; H, 6.01; N, 14.07. Found: C, 72.50; H, 5.83; N, 13.92.

Example 59 3-Acetyl-4-methyl-2-(2-naphthyl)-5-(4-pyridyl)-1H-pyrrole

mp 116-123° C.; ¹H-NMR (CDCl₃) δ 8.78 (br.s, 1H), 8.61-8.57 (m, 2H),7.95-7.84 (m, 4H), 7.60-7.53 (m, 3H), 7.39-7.35 (m, 2H), 2.47 (s, 3H),2.13 (s, 3H); MS (FAB) m/z 327 (M+H)⁺; Anal. Calcd. for C₂₂H₁₈N₂O0.2H₂O: C, 80.07; H, 5.62; N, 8.49. Found: C, 80.23; H, 5.67; N, 8.25.

Example 60 3-Acetyl-2-(4-formylphenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 97-100° C.; ¹H-NMR (CDCl₃) δ 10.06 (s, 1H), 9.21 (br.s, 1H), 8.58(d,J=5.9 Hz, 2H), 7.96 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.38 (d,J=5.9 Hz, 2H), 2.44 (s, 3H), 2.21 (s, 3H); MS (EI) m/z 304 (M⁺);

Eample 61 3-Acetyl-4-methyl-2-(1-naphthyl)-5-(4-pyridyl)-1H-pyrrole

mp 218-220° C.; ¹H-NMR (CDCl₃) δ 8.69 (s, 1H), 8.57 (d, J=6.2 Hz, 2H),8.00-7.92 (m, 2H), 7.78-7.68 (m, 1H), 7.60-7.48 (m, 3H), 7.42-7.33 (m,3H), 2.58 (s, 3H), 1.77 (s, 3H); MS (EI) m/z 326 (M)⁺.

Eample 623-Acetyl-2-{3-(4-fluorophenoxy)phenyl}-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 158-159° C.; ¹H-NMR (CDCl₃) δ 8.63-8.60 (m, 2H), 8.43 (br.s, 1H),7.45-7.38 (m, 1H), 7.34-7.32 (m, 2H), 7.20-7.17 (m, 1H), 7.07-7.02 (m,6H), 2.44 (s, 3H), 2.16 (s, 3H); MS (FAB) m/z 387 (M+H)⁺; Anal. Calcd.for C₂₄H₁₉N₂O₂F 0.1H₂O: C, 74.25; H, 4.98; N, 7.22. Found: C, 74.44; H,4.92; N, 6.84.

Example 63

3-Acetyl-2-{(4-methoxycarbonyl)phenyl}-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 187-189° C.; ¹H-NMR (CDCl₃) δ 9.25 (br.s, 1H), 8.54 (d, J=4.8 Hz,2H), 8.09 (d, J=8.1 Hz, 2H), 7.54 (d, J=8.1 Hz, 2H), 7.37 (d, J=4.8 Hz,2H), 3.93 (s, 3H), 2.43 (s, 3H), 2.15 (s, 3H); MS (FAB) m/z 335 (M+H)⁺;Anal. Calcd. for C₂₀H₁₈N₂O₃ 0.2H₂O: C, 71.08; H, 5.49; N, 8.29. Found:C, 71.25; H, 5.45; N, 8.03.

Example 64 3-Acetyl-4-methyl-2-(3-nitrophenyl)-5-(4-pyridyl)-1H-pyrrole

mp 214-217° C.; ¹H-NMR (CDCl₃) δ 9.35 (br.s, 1H), 8.57 (d, J=5.1 Hz,2H), 8.37 (t, J=1.9 Hz, 1H), 8.28-8.24 (m, 1H), 7.85-7.80 (m, 1H), 7.62(t, J=8.1 Hz, 1H), 7.39-7.35 (m, 2H), 2.44 (s, 3H), 2.25 (s, 3H); MS(FAB) m/z 335 (M+H)⁺; Anal. Calcd. for C₁₈H₁₅N₃O₃ H₂O: C, 63.71; H,5.05; N, 12.38. Found: C, 63.46; H, 4.56; N, 12.00.

Example 65 3-Acetyl-4-methyl-2-(3-pyridyl)-5-(4-pyridyl)-1H-pyrrole

mp 182-186° C.; ¹H-NMR (CDCl₃) δ 9.77 (br.s, 1H), 8.73-8.70 (m, 1H),8.60-8.54 (m, 3H), 7.86-7.81 (m, 1H), 7.40-7.34 (m, 3H), 2.47 (s, 3H),2.18 (s, 3H); MS (FAB) m/z 278 (M+H)⁺; Anal. Calcd. for C₁₇H₁₅N₃O0.8H₂O: C, 69.99; H, 5.74; N, 14.40. Found: C, 69.82; H, 5.28; N, 14.22.

Example 663-Acetyl-2-(3-chloro-4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 206-209° C.; ¹H-NMR (CDCl₃) δ 9.43 (br.s, 1H), 8.50 (br.d, J=6.2 Hz,2H), 7.55 (dd, J=6.9 Hz, 2.2 Hz, 1H), 7.37-7.32 (m, 3H), 7.21 (t, J=8.8Hz, 1H), 2.43 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z 328 (M+H)⁺; Anal.Calcd. for C₁₈H₁₄N₂OClF: C, 65.76; H, 4.29; N, 8.52. Found: C, 66.16; H,4.40; N, 8.26.

Example 67 3-Acetyl-4-methyl-5-(4-pyridyl)-2-vinyl-1H-pyrrole

mp 150-155° C.; ¹H-NMR (CDCl₃) δ 8.64 (dd, J=4.7 Hz, 1.8 Hz, 2H),8.65-8.60 (br.s, 1H), 7.32 (dd, J=4.7 Hz, 1.8 Hz, 2H), 7.20 (dd. J=17.5Hz, 11.4 Hz, 1H), 5.57 (d, J=17.5 Hz, 1H), 5.38 (d, J=11.4 Hz, 1H), 2.52(s, 3H), 2.43 (s, 3H); MS (EI) m/z 226 (M⁺).

Example 68 3-Acetyl-2-(4-chlorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 187.5-189.5° C.; ¹H-NMR (CDCl₃) δ 8.91 (br.s, 1H), 8.56 (br.d, J=6.2Hz, 2H), 7.48-7.40 (m, 4H), 7.35 (br.d, J=6.2 Hz, 2H), 2.44 (s, 3H),2.14 (s, 3H); MS (ESI) m/z 309 (M−H)⁻; Anal. Calcd. for C₁₈H₁₅N₂OCl: C,69.57; H, 4.86; N, 9.01. Found: C, 69.21; H, 5.01; N, 8.74.

Example 69 3-Acetyl-2-(2-furyl)-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 218-220° C.; ¹H-NMR (CDCl₃) δ 8.95 (br.s, 1H), 8.65 (br.d, J=6.2 Hz,2H), 7.48 (d, J=1.8 Hz, 1H), 7.37-7.34 (m, 2H), 7.21 (d, J=3.3 Hz, 1H),6.53 (dd, J=3.3 Hz, 1.8 Hz, 1H), 2.47 (s, 3H), 2.46 (s, 3H); MS (ESI)m/z 267 (M+H)⁺; Anal. Calcd. for C₁₆H₁₄N₂O₂: C, 72.17; H, 5.30; N,10.52. Found: C, 71.81; H, 5.40; N, 10.44.

Example 70 3-Acetyl-4-methyl-5-(4-pyridyl)-2-(3-thienyl)-1H-pyrrole

mp 240-244° C.; ¹H-NMR (CDCl₃) δ 8.94 (s, 1H), 8.55 (br.d, J=6.2 Hz,2H), 7.49-7.42 (m, 2H), 7.34 (br.d, J=6.2 Hz, 2H), 7.22 (dd, J=5.1 Hz,1.4 Hz, 1H), 2.46 (s, 3H), 2.18 (s, 3H); MS (ESI) m/z 283 (M+H)⁺; Anal.Calcd. for C₁₆H₁₄N₂OS 0.1H₂O: C, 67.63; H, 5.04; N, 9.86. Found: C,67.53; H, 4.93; N, 9.59.

Example 713-Acetyl-4-methyl-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-pyrrole

mp 169-172° C.; ¹H-NMR (CDCl₃) δ 9.10 (s, 1H), 8.53 (dd, J=4.4 Hz, 1.4Hz, 2H), 7.40-7.26 (m, 6H), 2.52 (s, 3H), 2.44 (s, 3H), 2.13 (s, 3H); MS(ESI) m/z 323 (M+H)⁺; Anal. Calcd. for C₁₉H₁₈N₂OS 0.2H₂O: C, 70.00; H,5.69; N, 8.59. Found: C, 69.95; H, 5.83; N, 8.38.

Example 72 3-Acetyl-2-(2-fluorophenyl)-4-methyl-5(4-pyridyl-1H-pyrrole

mp 220-222° C.; ¹H-NMR (CDCl₃) δ 8.76 (br.s, 1H), 8.60 (dd, J=4.7 Hz,1.4 Hz, 2H), 7.48-7.40 (m, 2H), 7.35 (dd, J=4.7 Hz, 1.4 Hz, 2H),7.29-7.17 (m, 2H), 2.47 (s, 3H), 2.16 (s, 3); MS (ESI) m/z 295 (M+H)⁺;Anal. Calcd. for C₁₈H₁₅N₂OF 0.2H₂O: C, 72.57; H, 5.21; N, 9.40. Found:C, 72.87; H, 5.14; N, 9.47.

Example 733-Acetyl-4-methyl-5-(4-pyridyl)-2-(4-trifluoromethylphenyl)-1H-pyrrole

mp 178.5-179.5° C.; ¹H-NMR (CDCl₃) δ 9.14 (bs, 1H), 8.57-8.53 (m, 2H),7.74-7.59 (m, 4H), 7.36 (dd, J=4.6 Hz, 1.7 Hz, 2H), 2.44 (s, 3H), 2.17(s, 3H); IR (KBr) 3200, 1640, 1600, 1460, 1425, 1320, 1170, 1130, 1070,1020, 950, 930cm⁻¹; MS (EI) m/z 344 (M⁺); Anal. Calcd for C₁₄H₁₅N₂OF₃0.2H₂O: C, 65.59; H, 4.46; N, 8.05. Found: C, 65.32; H, 4.40; N, 8.08.

Example 74 3-Acetyl-2-(4-methoxyphenyl)-4-methy-5-(4-pyridyl)-1H-pyrrole

mp 185-186° C.; ¹H-NMR (CDCl₃) δ 8.61 (dd, J=4.4 Hz, 1.8 Hz, 2H), 8.40(bs, 1H), 7.39 (dd, J=6.6 Hz, 2.2 Hz, 2H), 7.35 (dd, J=4.6, 1.7 Hz, 2H),6.99 (dd, J=6.8, 2.0 Hz, 2H), 3.87 (s, 3H), 2.47 (s, 3H), 2.11 (s, 3H);IR (KBr) 3200, 1600, 1490, 1460, 1420, 1405, 1280, 1250, 1180, 1040,840, 820 cm⁻¹; MS (EI) m/z 306 (M⁺); Anal. Calcd for C₁₉H₁₈N₂O₂ 0.3H₂O:C, 73.20; H, 6.01; N, 8.99. Found: C, 73.18; H, 5.79; N, 8.93.

Example 753-Acetyl-4-methyl-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-pyrrole

To a stirred solution of3-acetyl-4-methyl-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-pyrrole (0.24g, 0.74 mmol) in methanol (8 mL) was added a solution of NaIO₄ (0.6 g)in water (16 mL) at room temperature. After stirring for 15 hours, theprecipitates were collected by filtration. The filtrate was extractedwith CH₂Cl₂—EtOH (10:1, 50 mL×2), dried over MgSO₄, and concentrated inivacuo. The solids were purified by flash chromatography eluting withCH₂Cl₂—EtOH (10:1) to provide the title compound (0.24 g, quantitativeyield).

mp 249-250° C.; ¹H-NMR (CDCl₃) δ 10.8 (s, 1H), 8.56 (d, J=5.9 Hz, 2H),7.60 (d, J=8.1 Hz, 2H), 7.50-7.45 (m, 4H), 2.69 (s, 3H), 2.47 (s, 3H),2.18 (s, 3H); MS (ESI) m/z 339 (M+H)⁺; Anal. Calcd. for C₁₉H₁₈N₂O₂S0.2H₂O: C, 66.72; H, 5.42; N, 8.19. Found: C, 66.52; H, 5.64; N, 8.10.

Example 76 3-Acetyl-4-methyl-2-(4-morpholino)-5-(4-pyridyl)-1H-pyrrole

A mixture of 3-acetyl-2-bromo4-methyl-5-(4-pyridyl)-1H-pyrrole (1.6 g,5.74 mmol) and morpholine (12 mL) was heated at 135° C. for 12 hours.After cooling down, the precipitates were collected by filtration. Thefiltrate was purified by flash chromatography eluting with CH₂Cl₂—EtOH(10:1) to provide 0.72 g of yellow solids. Recrystallization from ethylacetate-EtOH provided the title compound (0.65 g, 40% yield).

mp 218-220° C.; ¹H-NMR (CDCl₃) δ 8.57 (br.s, 1H), 8.53 (d, J=5.9 Hz,2H), 7.26-7.23 (m, 2H), 3.89 (t, J=4.4Hz, 4H), 3.18 (t, J=4.4 Hz, 4H),2.55 (s, 3H); 2.42 (s, 3H); MS (FAB) m/z 286 (M+H)⁺; Anal. Calcd. forC₁₆H₁₉N₃O₂: C, 67.35; H, 6.71; N, 14.73. Found: C, 67.27; H, 7.07; N,14.77.

The compounds of example 77-81 were prepared according to the procedureof example 76 using the corresponding cyclic amines instead ofmorpholine.

Example 77 3-Acetyl-4-methyl-2-(1-piperidinyl -5-(4-pyridyl-1H-pyrrole

mp 204-207° C.; ¹H-NMR (CDCl₃) δ 8.55-8.52 (m, 2H), 8.23 (br.s, 1H),7.25-7.22 (m, 2H), 3.11 (t, J=5.1 Hz, 4H), 2.54 (s, 3H), 2.41 (s, 3H),1.77-1.61 (m, 6H); MS (FAB) m/z 284 (M+H)⁺; Anal. Calcd. for C₁₇H₂₁N₃O0.2H₂O: C, 71.15; H, 7.52; N, 14.64. Found: C, 71.23; H, 7.61;N, 14.36.

Example 783-Acetyl-4-methyl-2-(4-phenylpiperazin-1-yl)-5-(4-pyridyl)-1H-pyrrole

mp 218-220° C.; ¹H-NMR (CDCl₃) δ 8.57-8.53 (m, 2H), 8.46 (br.s, 1H),7.33-7.24 (m, 4H), 6.99-6.89 (m, 3H), 3.50-3.34 (m, 8H), 2.57 (s, 3H),2.43 (s, 3H); MS (FAB) m/z 361 (M+H)⁺; Anal. Calcd. for C₂₂H₂₄N₄O0.2H₂O: C, 72.58; H, 6.76; N, 15.39. Found: C, 72.52; H, 6.86;N, 15.15.

Example 793-Acetyl-2-{(1,4-dioxa-8-azaspiro[4.5]-decan)-8-yl}-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 200-203° C.; ¹H-NMR (CDCl₃) δ 8.55 (d, J=6.3 Hz, 2H), 8.25 (br.s,1H), 7.23 (d, J=6.3 Hz, 2H), 4.00 (s, 4H), 3.25 (t, J=5.1 Hz, 4H), 2.55(s, 3H), 2.42 (s, 3H), 1.92 (t, J=5.1 Hz, 4H); MS (FAB) m/z 342 (M+H)⁺;Anal. Calcd. for C₁₉H₂₃N₃O₃ 0.4H₂O: C, 65.46; H, 6.88; N, 12.05. Found:C, 65.32; H, 6.73; N, 12.30.

Example 803-Acetyl-2-(cis-2,6-dimethylmorpholin-4-yl)-4-methyl-5-(4-pyridyl)-1H-pyrrole

mp 95-100° C.; ¹H-NMR (CDCl₃) δ 9.42 (br.s, 1H), 8.43 (d, J=5.8 Hz, 2H),7.28-7.24 (m, 2H), 3.92-3.83 (m, 2H), 3.24 (br.s, 1H), 3.20 (br.s, 1H),2.72-2.62 (m, 2H), 2.53 (s, 3H), 2.41 (s, 3H), 1.20 (d, J=6.3 Hz, 6H);MS (EI) m/z 313 (M⁺);

Example 813-Acetyl-4-methyl-5-(4-pyridyl)-2-{4-(2-pyridyl)piperazin-1-yl}-1H-pyrrole

mp 89-92° C.; ¹H-NMR (CDCl₃) δ 8.75 (br.s, 1H), 8.51 (d, J=5.1 Hz, 2H),8.22 (d, J=4.0 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.24 (d, J=5.1 Hz, 2H),6.71-6.66 (m, 2H), 3.75-3.72 (m, 4H), 3.31-3.27 (m, 4H), 2.58 (s, 3H),2.42 (s, 3H); MS (ESI) m/z 362 (M+H)⁺; Anal. Calcd. for C₂₁H₂₃N₅O0.1H₂O: C, 69.44; H, 6.44; N, 19.28. Found: C, 69.14; H. 6.57; N, 18.98.

Example 824-Oxo-2-(4-pyridyl)-3,5,5trimethyl-4,5,6,7-tetrahydro-1H-indole and4-Oxo-2-(4-pyridyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

4-Oxo-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole and4-Oxo-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

The subtitle compounds were prepared according to the procedure ofExample 49 using 4,4-dimethylcyclohexane-1,3-dione instead ofcyclohexane-1,3-dione in step 1.

4-Oxo-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole

¹H-NMR (CDCl₃) δ 7.92 (br.s, 1H), 6.41 (s, 1H), 2.79 (t, J=6.2 Hz, 2H),2.29 (d, J=1.1 Hz, 3H), 1.97 (t, J=6.2 Hz, 2H), 1.18 (s, 6H).

4-Oxo-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

¹H-NMR (CDCl₃) δ 8.10 (br.s, 1H), 6.40 (d, J=1.1 Hz, 1H), 2.54 (t, J=6.2Hz, 2H), 2.29 (d, J=1.1 Hz, 3H), 1.96 (t, J=6.2 Hz, 2H), 1.34 (s, 6H).

2-Bromo-4-oxo-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole and2-Bromo-4-oxo-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

The subtitle compounds were prepared ccording to the procedure ofExample 45 (Method C) using4-oxo-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole and4-oxo-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole instead of3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

2-Bromo-4-oxo-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole

¹H-NMR (CDCl₃) δ 8.15 (br.s, 1H), 2.77 (t, J=6.3 Hz, 2H), 2.29 (s, 3H),1.97 (t, J=6.3 Hz, 2H), 1.17 (s, 6H).

2-Bromo-4-oxo-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

¹H-NMR (CDCl₃) δ 8.15 (br.s, 1H), 2.54 (t, J=6.3 Hz, 2H), 2.22 (d, J=1.1Hz, 3H), 1.96 (t, J=6.3 Hz, 2H), 1.34 (s, 6H).

4-Oxo-2-(4-pyridyl)-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole and4-Oxo-2-(4-pyridyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

The title compounds were prepared according to the procedure of Example45 (Method C) using2-bromo-4-oxo-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole and2-bromo-4-oxo-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole instead of3-acetyl-3-bromo-2,4-dimethyl-1H-pyrrole in step 2.

4-Oxo-2-(4-pyridyl)-3,5,5-trimethyl-4,5,6,7-tetrahydro-1H-indole

mp 237-239° C.; ¹H-NMR (CDCl₃) δ 8.77 (br.s, 1H), 8.59-8.56 (m, 2H),7.33-7.30 (m, 2H), 2.89 (t, J=6.2 Hz, 2H), 2.54 (s, 3H), 2.02 (t, J=6.2Hz, 2H), 1.21 (s, 6H); MS (FAB) m/z 255 (M+H)⁺; Anal. Calcd. forC₁₆H₁₈N₂O 0.3H₂O: C, 73.99; H, 7.22; N, 10.79. Found: C, 74.05; H, 7.15;N, 10.52.

4-Oxo-2-(4-pyridyl)-3,7,7-trimethyl-4,5,6,7-tetrahydro-1H-indole

mp 278-280° C.; ¹H-NMR (CDCl₃) δ 8.61-8.58 (m, 2H), 8.49 (br.s, 1H),7.33-7.28 (m, 2H), 2.58 (t, J=6.2 Hz, 2H), 2.54 (s, 3H), 2.00 (t, J=6.2Hz, 2H), 1.42 (s, 6H); MS (FAB) m/z 255 (M+H)⁺; Anal. Calcd. forC₁₆H₁₈N₂O 0.2H₂O: C, 74.51; H, 7.19; N, 10.86. Found: C, 74.53;H,7.31;N, 10.63.

Example 83 3-Methyl-4-oxo-2-(4-cyclohepteno(b)pyrrole

The title compounds were prepared according to the procedure of Example49 using cycloheptane-1,3-dione instead of cyclohexane-1,3-dione in step1.

3-Methyl-4-oxo-cyclohepteno(b)pyrrole

¹H-NMR (CDCl₃) δ 9.50 (br.s, 1H), 6.35 (s, 1H), 2.90-2.80 (m, 2H),2.70-2.60 (m, 2H), 2.26 (s, 3H), 1.95-1.85 (m, 4H).

2-Bromo-3-methyl-4-oxo-cyclohepteno(b)pyrrole

¹H-NMR (CDCl₃) δ 8.60 (br.s, 11H), 2.88 (t, J=5.9 Hz, 2H), 2.67 (t,J=5.5 Hz, 2H), 2.21 (s, 3H), 1.90-1.86 (m, 4H).

3-Methyl-4-oxo-2-(4-pyridyl)-cyclohepteno(b)pyrrole

mp 205-210° C.; ¹H-NMR (CDCl₃) δ 8.85 (br.s, 1H), 8.57-8.53 (m, 2H),7.32-7.25 (m, 2H), 3.00-2.95 (m, 2H), 2.73-2.68 (m, 2H), 2.48 (s, 3H),1.98-1.93 (m, 4H); MS (ESI) m/z 241 (M+H)⁺; Anal. Calcd. for C₁₅H₁₆N₂O0.5H₂O: C, 72.26; H, 6.87; N, 11.24. Found: C, 71.98; H, 6.46; N, 11.29.

Example 84 3-Acetyl-4-methyl-2-nitro-5-(4-pyridyl)-1H-pyrrole

To a cooled (−10˜−20° C.) acetic anhydride (1.2 mL) was added fumingnitric acid (0.13 mL) and sulfuric acid (1 drop). After stirring for 3minutes, 3-acetyl-4-methyl-5-(4-pyridyl)-1H-pyrrole (0.2 g, 1 mmol) wasadded to the mixture. The resulting mixture was allowed to warm to roomtemperature and stirred for additional 1 hour. The mixture was pouredinto saturated aqueous NaHCO₃. The whole was extracted with ethylacetate (30 mL×4), the combined organic layers washed with brine, driedover MgSO₄, and concentrated in vacito. The residue was purified byflash chromatography eluting with ethyl acetate-hexane (2:1) to providethe title compound (35 mg, 14% yield).

mp 187-188° C.; ¹H-NMR (CDCl₃) δ 10.95 (br.s, 1H), 8.67 (d, J=5.9 Hz,2H), 7.43-7.40 (m, 2H), 2.62 (s, 3H), 2.23 (s, 3H); MS (EI) m/z 245(M⁺); Anal. Calcd. for C₁₂H₁₁N₃O₃ 0.25H₂O: C, 57.71; H, 4.64; N, 16.83.Found: C, 58.23; H, 4.50; N, 16.28.

Example 85 2,4-Dimethyl-3-triflluoroacetiy-5-(4-pyridyl)-1H-pyrrole

2,4-Dimethyl-3-trifluoroacetyl-1H-pyrrole

According to the literature procedure (Chiswell, B. Inorganica ChimicaActa. 1972, 629), a mixture of anti-pyruvic aldehyde 1-oxime (1.3 g, 15mmol), 1,1,1-trifluoro-2,4-pentadione (1.85 mL, 15 mmol), glacial aceticacid (12 mL) and H₂O (3.0 mL) was stirred vigorously at roomtemperature. To this flask, zinc dust (3 g) was added slowly keeping thetemperature below 60° C. After addition, the resulting brown solutionwas heated under reflux condition for 2 hours. After cooling down toroom temperature, the reaction mixture was basified by an addition of 2M aqueous NaOH, then filtered. The filtrate was extracted with CH₂Cl₂(20 mL×3), the combined organic layer dried over MgSO₄, and concentratediii vacito. The residue was purified by flash chromatography (1-3:1CH₂Cl₂-Hexane) to afford the subtitle compound (0.42 g, 15% yield) as anoil.

¹H-NMR (CDCl₃) δ 8.15 (br. s, 1H), 6.41 (q, J=1.1 Hz, 1H), 2.52 (s, 3H),2.23 (t, J=1.1Hz, 3H); MS (EI) m/z 191 (M⁺);

2-Bromo-3,5-dimethyl-4-trifluoroacetyl-1H-pyrrole

The subtitle compound was prepared acording to the procedure of Example45 (Method C) using 2,4-dimethyl-3-trifluoroacetyl-1H-pyrrole instead of3-acetyl-2,4-dimethyl-1H-pyrrole in step 1.

¹H-NMR (CDCl₃) δ 8.45 (br. s, 1H), 2.50 (s, 3H), 2.19 (s, 3H); MS (EI)m/z 271 (M⁺), 269 (M⁺);

2,4-Dimethyl-3-trifluoroacetyl-5-(4-pyridyl)-1H-pyrrole

The title compound was prepared according to the procedure of Example 45(Method C) using 2-bromo-3,5-dimethyl-4-trifluoroacetyl-1H-pyrroleinstead of 3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.

mp 169-170° C.; ¹H-NMR (CDCl₃) δ 10.3 (br. s, 1H), 8.52 (d, J=4.8 Hz,2H), 7.34 (dd, J=4.6 Hz, 1.7 Hz, 2H), 2.61 (s, 3H), 2.42 (s, 3H); MS(EI) m/z 268 (M⁺); IR (KBr) 3000, 1665, 1605, 1475, 1440, 1425, 1280,1200, 1160, 1040, 1000, 920, 830, 735 cm⁻¹; Anal. Calcd for C₁₃H₁₁N₂OF:C, 58.21; H. 4.13; N, 10.44. Found: C, 57.91; H, 4.08; N, 10.37.

Example 86 3,6-Dimethyl-4-oxo-2-(4-pyridyl)-4,5,6,7-tetrahydro-1H-indole

According to the literature procedure (Chiswell, B. Inorganica ChimicaActa. 1972, 629), a mixture of 1-hydroxyimino-1-(4-pyridyl)-2-propanone(Tanaka, A et. al., Chem. Pharm. Bull., 1992, 40, 3206) (0.49 g, 3.0mmol), 5-methyl-1,3-cyclohexanedione (0.38 g, 3.0 mmol), glacial aceticacid (2.4 mL) and H₂O (0.6 mL) was stirred vigorously at roomtemperature. To this flask, zinc dust (0.6 g) was added slowly keepingthe temperature below 60° C. Afer addition, the resulting brown solutionwas heated under reflux condition for 2 hours. After cooling down toroom temperature, the reaction mixture was basified by an addition of 2M aqueous NaOH, then filtered. The filtrate was extracted with CH₂Cl₂(20 mL×3), the combined organic layer was dried over MgSO₄, andconcentrated in vacuo. The residue was purified by flash chromatography(1-5:1 EtOAc-Hexane then EtOAc only) to give the desired product (0.12g, 17% yield).

mp 247-248° C.; ¹H-NMR (CDCl₃) δ 8.59 (dd, J=4.6 Hz, 1.6 Hz, 3H), 7.31(dd, J=4.6 Hz, 1.6 Hz, 2H), 2.95-2.86 (m, 1H), 2.60-2.30 (m, 3H), 2.54(s, 3H), 2.30-2.19 (m, 1H), 1.16 (d, J=6.2 Hz, 3H); IR (KBr) 2950, 1650,1600, 1520, 1480, 1420, 1380, 1220, 1070, 995, 835, 680 cm⁻¹; MS (EI)m/z 240 (M⁺); Anal. Calcd for C₁₅H₁₆N₂O 0.1H₂O: C, 74.42; H, 6.74; N,11.57. Found: C, 74.18; H, 6.80; N,11.23.

Example 873-Methyl-4-oxo-2-(4-pyridyl)-6-thia-4,5,6,7-tetrahydro-1H-indole

According to the literature procedure (Chiswell, B. Inorganica ChimicaActa. 1972, 629), a mixture of 1-hydroxyimino-1-(4-pyridyl)-2-propanone(0.45 g, 2.7 mmol), thiacyclohexane-3,5-dione (Terasawa, T., Okada, T.,J. Org. Chem. 1977, 42, 1163) (0.39 g, 3.0 mmol), glacial acetic acid(2.4 mL) and H₂O (0.6 mL) was stirred vigorously at room temperture. Tothis flask, zinc dust (0.6 g) was added slowly keeping the temperaturebelow 60° C. After addition, the resulting brown solution was heatedunder reflux condition for 2 hours. After cooling down to roomtemperature, the reaction mixture was basified by an addition of 2 Maqueous NaOH, then filtered. The filtrate was extracted with CH₂Cl₂ (20mL×3), the combined organic layer dried over MgSO₄, and concentrated invacuo. The residue was purified by column chromatography (2-4:1 ethylacetate-Hexane then EtOAc only) then recystallization from hot ethylacetate and hexane to afford the title compound (0.10 g, 15% yield).

mp 209-210° C.; ¹H-NMR (CDCl₃) δ 8.98 (br s, 1H), 8.60 (dd, J=4.6, 1.7Hz, 2H), 7.31 (dd, J=4.6, 1.7 Hz, 2H), 3.86 (s, 2H), 3.41 (s, 2H), 2.52(s, 3H); IR (KBr) 2900, 2750, 1640, 1600, 1480, 1420, 1370, 1060, 1000,830 cm⁻¹; MS (EI) m/z 244 (M⁺); Anal. Calcd for C₁₃H₁₂N₂OS: C, 63.91; H.4.95; N, 11.47. Found: C, 64.11; H, 5.06; N, 11.37.

Example 88 3Acetyl-2-formyl-4-methyl-5-(4-pyridyl)-1H-pyrrole

3-Acetyl-2,4-dimethyl-5-(4-pyridyl)-1H-pyrrole (800 mg, 3.74 mmol) wasdissolved with THF (37 mL), acetic acid (45 mL) and water (37 mL).Ammonium cerium(IV) nitrate (8.38 g, 15.3 mmol) was added to the mixtureat room temperature and stirred for 1.5 hours. The mixture wasneutralized with 2 M aqueous NaOH solution and extracted with ethylacetate (150 mL×3). The combined organic layers were washed with brine,dried over MgSO₄, and evaporated in vacio. The residue was purified byflash chromatography eluting with ethyl acetate-hexane (2:1) to affordthe title compound (190 mg, 22% yield) as a solid.

mp: 208-209° C.; IR(KBr) ν 1660, 1600, 1470, 1430, 1280, 1250, 840 cm⁻¹;¹H-NMR (CDCl₃)δ 3 10.07 (s, 1H), 9.99 (s, 1H), 8.72 (dd, J=4.4 Hz, 1.5Hz, 2H), 7.39 (dd, J=4.4 Hz, 1.5 Hz, 2H), 2.65 (s, 3H), 2.45 (s, 3H);Anal. Calcd. for C₁₃H₁₂N₂O₂ 0.1H₂O: C, 67.87; H, 5.35; N, 12.18. Found:C, 67.81; H, 5.33; N, 11.95.

Example 89 3-Acetyl-2-hydroxymethyl-4-methyl-5-(4-pyridyl)-1H-pyrrole

To a stirred solution of3-acetyl-2-formyl-4-methyl-5-(4-pyridyl)-1H-pyrrole (84 mg, 0.37 mmol)in CH₂Cl₂ (2 mL) and methanol (2 mL) was added sodium borohydride (14mg, 0.37 mmol) at 0° C. and stirred for 30 minutes at room temperature.The mixture was poured into water (15 mL) and extracted with ethylacetate-ethanol (10:1, 20 mL×3). The combined organic layers were washedwith brine, dried over MgSO₄, and evaporated in vactio.Recrystallization from ethyl acetate provided the title compound (20 mg,24% yield) as a solid.

mp: 163-165° C.; ¹H-NMR (CDCl₃) δ 9.20 (s, 1H), 8.87-8.58 (m, 2H),7.35-7.20 (m, 2H), 4.80 (s, 2H), 2.53 (s, 3H), 2.48 (s, 3H); IR(KBr) ν1640, 1600, 1580, 1480, 1370, 1060, 1000, 940, 830 cm⁻¹; Anal. Calcd.for C₁₃H₁₄N₂O₂ 0.4H₂O: C, 65.75; H, 6.28; N, 11.80. Found: C, 65.97; H,6.16;N, 11.53.

Example 90 4-Methyl-3-(3-methylbutanoyl)-2,5-di(4-pyridyl)-1H-pyrrole

The title compound was prepared according to the procedure of Example 1using 6-methyl-2,4-heptanedione instead of 2,4-pentanedione.

mp 199-201° C.; ¹H-NMR (DMSO-d₆) d 11.96 (br.s, 1H), 8.68-8.52 (m, 4H),7.58-7.40 (m, 4H), 2.35 (d, J=7.0 Hz, 2H), 2.31 (s, 3H), 2.08-1.90 (m,1H), 0.75 (d, J=6.6 Hz, 6H); Anal. Calcd. for C₂₀H₂₁N₃O: C, 75.21 H,6.63; N, 13.16. Found: C, 75.08; H, 6.61; N, 13.19.

Example 91 Methyl 4-Methyl-2-phenyl-5-(4-pyridyl)pyrrole-3-carboxylate

Methyl 4-Methyl-2-phenylpyrrole-3-carboxylate

A mixture of N-(benzotriazol-1-yl-methyl)-α-(methylthio)phenylimine(Katritzky, A. R. et. al., Tetrahedron, 1995, 51, 13271) (1.65 g, 5.84mmol), methyl 3-oxobutanoate (878 mg, 8.77 mmol) and 60% NaH in oil (701mg, 17.5 mmol) in THF (20 mL) and DMSO (5 mL) was stirred for 4 hours atroom temperature. An excess NaH was quenched with water carefully. Themixture was diluted with diethyl ether (150 mL), washed with aqueous 10%NaOH (50 mL×3), dried over MgSO₄, and concentrated in vaczio. Theresidue was purified by flash chromatography eluting with ethylacetate-hexane (1:5) to afford the subtitle compound (973 mg, 78% yield)as an oil.

¹H-NMR (CDCl₃) δ:8.31 (s, 1H), 7.47-7.25 (m, 5H), 6.53 (s, 1H), 3.67 (s,3H), 2.29 (s, 3H).

Methyl 5-Bromo-4-methyl-2-phenylpyrrole-3-carboxylate

To a solution of methyl 4-methyl-2-phenylpyrrole-3-carboxylate (74 mg,0.341 mmol) in TEF (1.5 mL) was added NBS (67 mg, 0.375 mmol) at −78° C.After being stirred for 0.25 hour at the same temperature, the mixturewas allowed to warm to room temperature. The mixture was poured intoice-water (5 mL). The whole was extracted with ethyl acetate (20 mL),dried over Na₂SO₄ and concentrated in vacuo. The residual oil waspurified by flash chromatography eluting with ethyl acetate-hexane (1:8)to afford the subtitle compound (97 mg, 96% yield) as crystals.

¹H-NMR (CDCl₃) δ:8.44 (br.s, 1H), 7.43-7.25 (m, 5H), 3.66 (s, 3H), 2.23(s, 3H).

Methyl 4-Methyl-2-phenyl-5-(4-pyridyl)pyrrole-3-carboxylate

A mixture of methyl 5-bromo-4-methyl-2-phenylpyrrole-3-carboxylate (82mg, 0.278 mmol), 4-pyridylboronic acid (68 mg, 0.556 mmol), PdCl₂(PPh₃)₂(20 mg, 0.0278 mmol), and saturated aqueous NaHCO₃ (0.3 mL) indimethoxyethane (1.5 mL) was refluxed for 16 hours. The mixture wasextracted with CH₂Cl₂ (10 mL×3), the combined organic layer dried overNa₂SO₄, and concentrated ini vacito. The residue was purified by PTLC (1mm) with acetone-hexane (1:2) to afford the title compound (37 mg, 46%yield).

mp: 202-204° C.; ¹H-NMR (CDCl₃) δ: 9.72 (br.s, 1H), 8.46 (br.s, 2H),7.66-7.26 (m, 7H), 3.70 (s, 3H), 2.49 (s, 3H); IR(KBr) ν: 3450, 1700,1600, 1470, 1440, 1260, 1080, 700 cm⁻¹; MS (EI) m/z 292 (M⁺); Anal.Calcd. for C₁₈H₁₅N₃O₂ 0.2C₄H₁₀O 0.1H₂O: C; 73.09, H; 5.94, N; 9.07;Found: C, 73.12, H; 5.44, N; 8.72.

Example 92(6RS)-6-Methyl-1,3-di(4-pyridyl)-6,7-dihydro-2H-pyrano[3.4-c]-4-one

A mixture of 4-pyridinecarboxaldehyde (2.09 g, 19.5 mmol),5,6-dihydro-4-hydroxy-6-methyl-2H-pyran-2-one (1.00 g, 7.80 mmol), and25% ammonia solution (2.0 mL) in ethanol (5 mL) was refluxed for 7hours. After cooling to room temperature, the mixture was concentratedini vacuo. The residual oil was purified by flash chromatography elutingwith methanol-CH₂Cl₂(1:15) to afford 108 mg. Recrystallized form ethylacetate-hexane gave the title compound (60 mg, 2.5% yield).

mp: >280° C.; ¹H-NMR (DMSO-d₆) δ: 12.39 (br.s, 1H), 8.53-8.46 (m, 4H),7.26-7.13 (m, 4H), 4.74 (ddq, J=, 11.4, 6.2, and 3.9 Hz, 1H), 3.04 (dd,J=16.5 and 3.9 Hz, 1H), 2.88 (dd, J=16.5 and 11.4 Hz, 1H), 1.44 (d,J=6.2 Hz, 3H); IR(KBr) ν: 3450, 1680, 1600, 1580, 1480, 1420, 1380,1080, 1040, 820 cm⁻¹; Anal. Calcd. for C₁₈H₁₅N₃O₂ 0.2 C₄H₈O₂: C; 69.92,H; 5.18, N; 13.01. Found: C; 69.54, H; 5.19, N; 13.01

Example 93 Ethyl 2,4-Dimetyl-5-(4-pyridyl)pyrrole-3-carboxylate

The title compound was prepared according to the procedure of Example 45(Method C) using ethyl 5-bromo-2,4-dimetylpyrrole-3-carboxylate(Cordell, G. A, J. Org. Chem., 1975, 40, 3161) instead of3-acetyl-5-bromo-2,4-dimethyl-1H-pyrrole in step 2.

mp: 180-181.5° C.; ¹H-NMR (CDCl₃) δ: 9.18 (br.s, 1H), 8.54(d, J=4.4Hz,1H), 8.53 (d, J=4.8 Hz, 1H), 7.31 (d, J=4.8 Hz, 1H), 7.30 (d, J=4.4 Hz,1H), 4.31 (q, J=7.0 Hz, 2H), 2.57 (s, 3H), 2.47 (s, 3 H), 1.37 (t, J=7.0Hz, 3H); IR(KBr) ν: 3450, 1690, 1600, 1430, 1260, 1100, 1000, 830 cm⁻¹;Anal. Calcd for C₁₄H₁₆N₂O₂ 0.1H₂O: C; 68.33, H; 6.64, N; 11.38. Found:C; 68.00, H; 6.66, N; 11.30.

Example 94 Methyl2-(2-Methoxyethyl)-4-methyl-5-(4-pyridyl)pyrrole-3-carboxyalte

To a solution of 1-hydroxyimino-1-(4-pyridyl)-2-propanone (500 mg, 3.05mmol) in glacial acetic acid (18 mL) was added methyl5-methoxy-3-oxopentanoate (634 mg, 3.96 mmol) at room temperature. Znpowder (597 mg, 9.14 mmol) was added to the mixture at room temperatureand the mixture was heated for 1 hour at 100° C. The mixture wasfiltered through a pad of Celite and the pad was washed with acetic acidthoroughly. The filtrate was evaporated to give a oily residue, whichwas purified by flash chromatography eluting with acetone-hexane (1:2)to afford the title compound (220 mg, 26% yield).

mp: 177-179° C.; ¹H-NMR (CDCl₃) δ: 9.81 (br.s, 1H), 8.56-8.53 (m, 2H),7.29-7.27 (m, 2H), 3.83 (s, 3H), 3.72 (t, J=5.7 Hz, 2H), 3.41 (s, 3H),3.29 (t, J=5.7 Hz, 2 H), 2.45 (s, 3H); IR(KBr) ν: 3450, 1690, 1610,1480, 1360, 1260, 1120, 1000, 830 cm⁻¹; Anal. Calcd. for C₁₅H₁₈N₂O₃: C;65.68, H; 6.61, N; 10.21. Found: C; 65.79, H; 6.65, N; 10.13.

Example 95 Metyl 2,5-di(4-Pyridyl)pyrrole-3-carboxylate

The title compound was prepared according to the procedure of Example 10using methyl 3-methoxyacrylate instead of ethyl propionylacetate.

mp: >270° C.; ¹H-NMR (DMSO-d6) δ: 12.40 (br.s, 1H), 8.53 (d, J=5.9 Hz,2H), 8.42 (d, J=6.2 Hz, 2H), 7.75 (s, 1H), 7.23 (d, J=4.8 Hz, 2H), 7.09(d, J=5.5 Hz, 2H), 3.66 (s, 3H); IR(KBr) ν: 3450, 1700, 1600, 1430,1420, 1350, 1190, 830 cm⁻¹; Anal. Calcd. for C₁₆H₁₃N₃O₂ 0.5 H₂CO₃: C;63.87, H; 4.55, N; 13.54. Found: C; 63.56, H; 4.45, N; 13.81.

In addition, the chernical structures of the compounds prepared in theabove Working Examples are summarized in the following Table. In Table,the following abbreviations are used: Me for methyl, Et for ethyl or Phfor phenyl, and R² is attached to the 4-position of the pyrrole ring andR³ is attached to the 3-position of the pyrrole ring.

Ex. R¹ R² R³ R⁴ (R⁵)_(m)  1 H Me acetyl 4-pyridyl —  2 H Me acetyl4-pyridyl — (dihydrochloride monohydrate)  3 H Et propanoyl 4-pyridyl — 4 H F₃C— acetyl 4-pyridyl —  5 H Me propanoyl 4-pyridyl —  6 H Mepentanoyl 4-pyridyl —  7 H phenyl acetyl 4-pyridyl —  8 H Me acetyl4-quinolyl (CH═CH—CH═CH)—  9 H Me acetyl 4-pyridyl (CH═CH—CH═CH)— 10 HEt Et—O—C(O)— 4-pyridyl — 11 H Me Et—O—C(O)— 4-pyridyl — 12 H MeMe—O—C(O)— 4-pyridyl — 13 H Me Ph—CH₂—O—C(O)— 4-pyridyl — 14 H Meallyloxy-C(O)— 4-pyridyl — 15 H Me (CH₃)₂CH—O—C(O)— 4-pyridyl — 16 H Me(CH₃)₃C—O—C(O)— 4-pyridyl — 17 H Me CH₃(CH₂)₂O—C(O)— 4-pyridyl — 18 H PhEt—O—C(O)— 4-pyridyl — 19 H Me butoxy-C(O)— 4-pyridyl — 20 H MeMeO(CH₂)₂O—C(O)— 4-pyridyl — 21 H propyl Et—O—C(O)— 4-pyridyl — 22 H(CH₃)₂CH— Et—O—C(O)— 4-pyridyl — 23 H butyl Et—O—C(O)— 4-pyridyl — 24 HMeO—CH₂— Me—O—C(O)— 4-pyridyl — 25 H nitro-Ph Et—O—C(O)— 4-pyridyl — 26H Me formyl 4-pyridyl — 27 H Me methanesulfonyl 4-pyridyl — 28 H Etacetyl 4-pyridyl — 29 H propyl acetyl 4-pyridyl — 30 H (CH₃)₂CH— acetyl4-pyridyl — 31 H butyl acetyl 4-pyridyl — 32 H MeO—CH₂— acetyl 4-pyridyl— 33 H HO—CH₂— acetyl 4-pyridyl — 34 H Me CH₃CH(OH)— 4-pyridyl — 35 H MeCH₃O—N═C(CH₃)— 4-pyridyl — (hydrogen chloride) 36 H Me acetyl 4-pyridyl— (N,N′-dioxide) H Me acetyl 4-pyridyl — (mixture of N-oxide andN′-oxide) 37 Me—O—CH₂— Me acetyl 4-pyridyl — 38 Me—O—(CH₂)₂— Me acetyl4-pyridyl — 39 H Me HO—CH₂— 4-pyridyl — 40 H Me H₂N—C(O)— 4-pyridyl — 41H Me HOOC— 4-pyridyl — (morpholinium) 42 H 4-pyridyl acetyl Me — 43 H Hacetyl Me — 44 H Et—O—C(O)— Me Ph — 45 H Me acetyl Me — 46 H Me acetylPh — 47 H acetyl Me Ph — 48 H Me acetyl H — 49 H Me C(O)—CH₂—CH₂—CH₂— —50 H Me acetyl Br — 51 H Me acetyl F—Ph — 52 H Me acetyl 2-thienyl — 53H CH₂—CH₂—CH₂—C(O)— Ph — 54 H C(O)—CH₂—CH₂—CH₂— Ph — 55 H MeC(O)—CH₂—C(CH₃)₂—CH₂— — 56 H Me C(O)—CH₂—CHPh—CH₂— — 57 H Me cyano4-pyridyl — 58 H Me acetyl 3-amino-Ph — 59 H Me acetyl 2-naphthyl — 60 HMe acetyl 4-formyl-Ph — 61 H Me acetyl 1-naphtyl — 62 H Me acetyl3-(4-F—Ph—O—)—Ph — 63 H Me acetyl 4-Me—O—C(O)—Ph — 64 H Me acetyl3-nitro-Ph — 65 H Me acetyl 3-pyridyl — 66 H Me acetyl 3-Cl, 4-F—Ph — 67H Me acetyl vinyl — 68 H Me acetyl 4-Cl—Ph — 69 H Me acetyl 2-furyl — 70H Me acetyl 3-thienyl — 71 H Me acetyl 4-Me—S—Ph — 72 H Me acetyl2-F—Ph— — 73 H Me acetyl 4-F₃C—Ph — 74 H Me acetyl 4-Me—O—Ph— — 75 H Meacetyl 4-Me—S(O)—Ph — 76 H Me acetyl 4-morpholino — 77 H Me acetyl1-piperidinyl — 78 H Me acetyl 4-Ph-piperazin-1-yl — 79 H Me acetyl(1,4-dioxa-8-azaspiro — [4,5]-decan)-8-yl 80 H Me acetylcis-2,6-dimethyl — morpholin-4-yl 81 H Me acetyl 4-(2-pyridyl) —piperazin-1-yl 82 H Me —C(O)C(CH₃)₂(CH₂)₂— — H Me —C(O)(CH₂)₂C(CH₃)₂— —83 H Me —C(O)(CH₂)₄— — 84 H Me acetyl nitro — 85 H Me CF₃C(O)— Me — 86 HMe —C(O)CH₂CH(CH₃)CH₂— — 87 H Me —C(O)CH₂—S—CH₂— — 88 H Me acetyl formyl— 89 H Me acetyl OH—CH₂— — 90 H Me (CH₃)₂CHCH₂C(O)— 4-pyridyl — 91 H MeCH₃OC(O)— Ph — 92 H —C(O)—O—CH(CH₃)CH₂— 4-pyridyl — 93 H Me EtOC(O)— Me— 94 H MeO(CH₂)₂— MeOC(O)— Me — 95 H Me MeOC(O)— H —

What is claimed is:
 1. A compound of the formula:

and its pharmaceutically acceptable salts, wherein R¹ is selected fromthe following: (a) hydrogen, R⁶—, R⁶—NH—, hydroxy-R⁶— or R⁶—O—R⁶—; (b)R⁶—CO—, R⁶—O—CO—R⁶—, carboxy-R⁶—, NH₂—CO— or R⁶—NH—CO—; and (c) Ar—,Ar—R⁶—, Ar—NH— or Ar—CO—; wherein Ar is selected from phenyl, naphthyl,pyridyl, quinolyl, thienyl, flryl, pyrrolyl, indolyl, benzothienyl andbenzofuryl, the aryl or heteroaryl groups being optionally substitutedwith one or two substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro,hydroxy, amino, R⁶—NH—, (R⁶)₂N—, halo, formyl, halo-substituted phenoxy,halo-substituted phenyl, C₁₋₄ alkyl-substituted phenoxy,halo-substituted phenylthio, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylthio andC₁₋₄ alkyl-SO—; provided R¹ is not quinolyl; and wherein R⁶ is C₁₋₆alkyl optionally substituted by up to four halogen atoms; R² is selectedfrom the following: (d) hydrogen, halo, R⁶—, C₂₋₆ alkenyl, C₂₋₆ alkynyl,hydroxy-R⁶—, R⁶—O—R⁶—, mercapto-R⁶—, R⁶—S—R⁶—, —NH₂, R⁶—NH—, (R⁶)₂—N—,R⁶—O—, R⁶—S—, R⁶—SO— and R⁶—SO₂—; (e) 1,4-dioxa-8-azaspiro[4,5]-decanyl,

wherein Y is selected from —NH, —N—R⁶, —N—Ar, O and S; l is 0, 1, 2, 3,4 or 5; n is independently 0, 1 or 2; and Ar is as defined above; (f)Ar—, Ar—R⁶—, Ar—C₂₋₆ alkenyl, Ar—C₂₋₆ alkynyl, Ar—O—, Ar—O—R⁶—,Ar—R⁶—O—, Ar—S—, Ar—R⁶—S—, Ar—NH—, (Ar)₂—R⁶—, Ar—R⁶—NH— or (Ar)₂—N—; (g)R⁶—CO—, —NO₂, NH₂—CO—, R⁶—NH—CO—, (R⁶)₂—N—CO—, Ar—CO—, (Ar—R⁶)₂—N—CO—,Ar—R⁶—CO—, Ar—NH—CO— or Ar—R⁶—NH—CO—; and (h) R⁶—CO—NH—, Ar—CO—NH—,Ar—R⁶—CO—NH— or H₂N—CO—NH—; wherein Ar and R⁶ are as defined above,provided that R² is not Ar; R is R⁶—CO—; R⁴ is pyridyl wherein saidpyridyl may optionally be substituted with one or two substituentsindependently selected from C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo,formyl, fluorophenoxy, methoxycarbonyl, ethoxycarbonyl, methylthio,ethylthio and methyl-SO—; R⁵ is independently selected from thefollowing: (n) hydrogen, halo, R⁶—, hydroxy-R⁶— or R⁶—O—R⁶—; (o) Ar—,Ar—R⁶—, Ar—O—, Ar—S—, Ar—NH— or Ar—CO—; and (p) R⁶—CO—, R⁶—CO— orR⁶—NH—CO—; or two of R⁵ which are attached to adjacent carbon atoms onthe pyridine ring complete a fused benzene ring, the benzene ring beingoptionally substituted with one or two substituents selected from C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro,hydroxy, amino and halo; wherein R⁶ and Ar are as defined above; m is 0,1, 2, 3 or 4; R³ is at position 3; and the nitrogen atom of the pyridylring attached to the 5-position of the pyrrole ring is optionallyreplaced by a N oxide group.
 2. A compound according to claim 1, whereinR¹ is selected from group (a); R² is selected from group (d), (e) or(f), provided that R² is not Ar; and R¹ is selected from group (n); andm is 0, 1 or
 2. 3. A compound according to claim 2, wherein R¹ ishydrogen, C₁₋₄ alkyl, C₁₋₄ alkylamino, halo substituted C₁₋₄ alkyl,hydroxy-C₁₋₄ alkyl, C₁₋₄ alkoxyalkyl or halo C₁₋₄ alkoxy-C₁₋₄ alkyl; R²is hydrogen, halo, R⁶—, hydroxy-R⁶— or R⁶—O—R⁶—; R⁵ is hydrogen, halo,C₁₋₄ alkyl or halo substituted C₁₋₄ alkyl; and m is 0 or
 1. 4. Acompound according to claim 3, wherein R¹ is hydrogen, C₁₋₄ alkyl orC₁₋₄ alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, C₁₋₄ alkyl optionallysubstituted by halo, hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ isC₁₋₄ alkylcarbonyl; and R⁵ is hydrogen or halo.
 5. A compound accordingto claim 4, wherein R¹ is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₄alkyl; R² is C₁₋₄ alkyl optionally substituted by halo, hydroxy-C₁₋₄alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ is C₁₋₄ alkylcarbonyl; R⁴ isoptionally substituted with C₁₋₄ alkoxy, halo, formyl, 4-fluorophenoxy,methoxycarbonyl, ethoxycarbonyl or methylthio; and R⁵ is hydrogen.
 6. Acompound according to claim 1, wherein R¹ is hydrogen, methyl ormethoxyethyl; R² is methyl, ethyl, monofluoromethyl, difluoromethyl,trifluoromethyl, phenyl, n-propyl, isopropyl, n-bytyl, isobutyl,methoxymethyl, nitrophenyl, hydroxymethyl or pyridyl; R³ is acetyl,propanoyl, or pentanoyl; R² is at the 4 position of the pyrrole ring; R⁴is pyridyl; and R⁵ is hydrogen.
 7. A compound according to claim 1,being one of the following:3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole;3-acetyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole;3-acetyl-2,5-di(4-pyridyl)-4-trifluoromethyl-1H-pyrrole.
 8. A processfor preparing a compound of the formula:

wherein R¹, R⁵ and m are defined in claim 1; R^(2a) are independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Ar or Ar—C₁₋₄ alkyl;and R⁷ is —C(O)R^(3a), —C(O)OR^(3a), —CN or —SO₂R^(3a), wherein R^(3a)is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Ar or Ar—C₁₋₄alkyl, which comprises reacting a compound of the formula:

 with a compound of the formula:

and amine R¹NH₂ in a reaction-inert solvent.
 9. A pharmaceuticalcomposition for the treatment of cytokine-mediated diseases or CAMsmediated diseases, which comprises a therapeutically effective amount ofa compound of the formula:

and its pharmaceutically acceptable salts, wherein R¹ is selected fromthe following: (a) hydrogen, R⁶—, R⁶—NH—, hydroxy-R⁶— or R⁶—O—R⁶—; (b)R⁶—CO—, R⁶—O—CO—R⁶—, carboxy-R⁶—, NH₂—CO— or R⁶—NH—CO—; and (c) Ar—,Ar—R⁶—, Ar—NH— or Ar—CO—; wherein Ar is selected from phenyl, naphthyl,pyridyl, quinolyl, thienyl, furyl, pyrrolyl, indolyl, benzothienyl andbenzofuryl, the aryl or heteroaryl groups being optionally substitutedwith one or two substituents selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,halo-substituted C₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro,hydroxy, amino, R⁶—NH—, (R⁶)₂N—, halo, formyl, halo-substituted phenoxy,halo-substituted phenyl, C₁₋₄ alkyl-substituted phenoxy,halo-substituted phenylthio, C₁₋₄ alkoxycarbonyl, C₁₋₄ alkylthio andC₁₋₄ alkyl-SO—; provided R¹ is not quinolyl; and wherein R⁶ is C₁₋₆alkyl optionally substituted by up to four halogen atoms; R² is selectedfrom the following: (d) hydrogen, halo, R⁶—, C₂₋₆ alkenyl, C₂₋₆ alkynyl,hydroxy-R⁶—, R⁶—O—R⁶—, mercapto-R⁶—, R⁶—S—R⁶—, —NH₂, R⁶—NH—, (R⁶)₂—N—,R⁶—O—, R⁶—S—, R⁶—SO— and R⁶—SO₂—; (e) 1,4-dioxa-8-azaspiro[4,5]-decanyl,

wherein Y is selected from —NH, —N—R⁶, —N—Ar, 0 and S; l is 0, 1, 2, 3,4 or 5; n is independently 0, 1 or 2; and Ar is as defined above; (f)Ar—, Ar—R⁶—, Ar—C₂₋₆ alkenyl, Ar—C₂₋₆ alkynyl, Ar—O—, Ar—O—R⁶—,Ar—R⁶—O—, Ar—S—, Ar—R⁶—S—, Ar—NH—, (Ar)₂—R⁶—, Ar—R⁶—NH— or (Ar)₂—N—; (g)R⁶—CO—, —NO₂, NH₂—CO—, R⁶—NH—CO—, (R⁶)₂—N—CO—, Ar—CO—, (Ar—R⁶)₂—N—CO—,Ar—R⁶—CO—, Ar—NH—CO— or Ar—R⁶—NH—CO—; and (h) R⁶—CO—NH—, Ar—CO—NH—,Ar—R⁶—CO—NH— or H₂N—CO—NH—; wherein Ar and R⁶ are as defmed above,provided that R² is not Ar; R³ is R⁶—CO—; R⁴ is pyridyl wherein saidpyridyl may optionally be substituted with one or two substituentsindependently selected from C₁₋₄ alkyl, hydroxy, C₁₋₄ alkoxy, halo,formyl, fluorophenoxy, methoxycarbonyl, ethoxycarbonyl, methylthio,ethylthio and methyl-SO—; R⁵ is independently selected from thefollowing: (n) hydrogen, halo, R⁶—, hydroxy-R⁶— or R⁶—O—R⁶—; (o) Ar—,Ar—R⁶—, Ar—O—, Ar—S—, Ar—NH— or Ar—CO—; and (p) R⁶—CO—, R⁶—O—CO— orR⁶—NH—CO—; or two of R⁵ which are attached to adjacent carbon atoms onthe pyridine ring complete a fused benzene ring, the benzene ring beingoptionally substituted with one or two substituents selected from C₁₋₄alkyl, halo-substituted C₁₋₄ alkyl, halo-substituted C₁₋₄ alkoxy, nitro,hydroxy, amino and halo; wherein R⁶ and Ar are as defined above; m is 0,1, 2, 3 or 4; R³ is at position 3; and the nitrogen atom of the pyridylring attached to the 5-position of the pyrrole ring is optionallyreplaced by a N oxide group.
 10. A pharmaceutical composition accordingto claim 9, wherein R¹ is selected from group (a); R² is selected fromgroup (d), (e) or (f), provided that R² is not Ar; and R⁵ is selectedfrom group (n); and m is 0, 1 or
 2. 11. A pharmaceutical compositionaccording to claim 10, wherein R¹ is hydrogen, C₁₋₄ alkyl, C₁₋₄alkylamino, halo substituted C₁₋₄ alkyl, hydroxy-C₁₋₄ alkyl, C₁₋₄alkoxyalkyl or halo C₁₋₄ alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, R⁶—,hydroxy-R⁶— or R⁶—O—R⁶—; R⁵ is hydrogen, halo, C₁₋₄ alkyl or halosubstituted C₁₋₄ alkyl; and m is 0 or
 1. 12. A pharmaceuticalcomposition according to claim 11, wherein R¹ is hydrogen, C₁₋₄ alkyl orC₁₋₄ alkoxy-C₁₋₄ alkyl; R² is hydrogen, halo, C₁₋₄ alkyl optionallysubstituted by halo, hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R³ isC₁₋₄ alkylcarbonyl; and R⁵ is hydrogen or halo.
 13. A pharmaceuticalcomposition according to claim 12, wherein R¹ is hydrogen, C₁₋₄ alkyl orC₁₋₄ alkoxy-C₁₋₄ alkyl; R² is C₁₋₄ alkyl optionally substituted by halo,hydroxy-C₁₋₄ alkyl or C₁₋₄-alkoxy-C₁₋₄ alkyl; R⁴ is optionallysubstituted with C₁₋₄ alkoxy, halo, formyl, 4-fluorophenoxy,methoxycarbonyl, ethoxycarbonyl or metht and R⁵ is hydrogen.
 14. Apharmaceutical composition according to claim 10, wherein R¹ ishydrogen, methyl or methoxyethyl; R² is methyl, ethyl, monofluoromethyl,difluoromethyl, trifluoromethyl, phenyl, n-propyl, isopropyl, n-bytyl,isobutyl, methoxymethyl, nitrophenyl, hydroxymethyl or pyridyl; R³ isacetyl, propanoyl, or pentanoyl; R⁴ is pyridyl; and R⁵ is hydrogen. 15.A pharmaceutical composition according to claim 10, comprising acompound selected from: 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole;3-acetyl-4-ethyl-2,5-di(4-pyridyl)-1H-pyrrole;3-acetyl-2,5-di(4-pyridyl)-4-trifluoromethyl-1H-pyrrole.
 16. Apharmaceutical composition for the treatment of arthritis, sepsis,septic shock, psoriasis, and crohn's disease, which comprises atherapeutically effective amount of a compound of claim 1 and itspharmaceutically acceptable carrier.
 17. A method for the treatment ofdisease conditions caused by cytokine-mediated diseases or CAMs mediateddiseases, in a mammalian subject, which comprises administering to saidsubject a therapeutically effective amount of a compound according toclaim
 1. 18. A method for the treatment of arthritis, sepsis, septicshock, psoriasis, and crohn's disease, which comprises administering tosaid subject a therapeutically effective amount of a compound accordingto claim 1.